3-(Carboxymethyl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives

ABSTRACT

The invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

This application is a continuation of U.S. Non-Provisional patentapplication Ser. No. 16/454,489, filed Jun. 27, 2019; now allowed, whichis a continuation of U.S. Non-Provisional patent application Ser. No.16/212,723, filed Dec. 7, 2018, abandoned, which is a continuation ofU.S. Non-Provisional patent application Ser. No. 15/980,181, filed May15, 2018, abandoned, which is a continuation of U.S. Non-Provisionalpatent application Ser. No. 15/405,919, filed Jan. 13, 2017, abandoned,which claims foreign priority of European Patent Application No. 16 151014.4, filed Jan. 13, 2016, the disclosures of which are incorporatedherein by reference.

The invention relates to3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decanederivatives, their preparation and use in medicine, particularly invarious neurological disorders, including but not limited to pain,neurodegenerative disorders, neuroinflammatory disorders,neuropsychiatric disorders, substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which arewidely distributed in the human body. The opioid receptors are currentlysubdivided into four major classes, i.e. the three classical opioidreceptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, anddelta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1)receptor, which was more recently discovered based on its high homologywith said classical opioid receptors. After identification of theendogenous ligand of the ORL-1 receptor, known as nociceptin/orphaninFQ, a highly basic 17 amino acid peptide isolated from tissue extractsin 1995, the ORL-1 receptor was renamed “nociceptin opioid peptidereceptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOPreceptor are widely distributed/expressed in the human body, includingin the brain, the spinal cord, on peripheral sensory neurons and theintestinal tract, wherein the distribution pattern differs between thedifferent receptor classes.

Nociceptin acts at the molecular and cellular level in very much thesame way as opioids. However, its pharmacological effects sometimesdiffer from, and even oppose those of opioids. NOP-receptor activationtranslates into a complex pharmacology of pain modulation, which,depending on route of administration, pain model and species involved,leads to either pronociceptive or antinociceptive activity. Furthermore,the NOP receptor system is upregulated under conditions of chronic pain.Systemic administration of selective NOP receptor agonists was found toexert a potent and efficacious analgesia in non-human primate models ofacute and inflammatory pain in the absence of side effects. Theactivation of NOP receptors has been demonstrated to be devoid ofreinforcing effects but to inhibit opioid-mediated reward in rodents andnon-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171(16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results frompreclinical experiments suggest that NOP receptor agonists might beuseful inter alia in the treatment of neuropsychiatric disorders (Witkinet al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al.,Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOPreceptor is also implicated to modulate not only pain but alsoneuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treatmoderate to severe acute and chronic pain. However, the therapeuticwindow of strong opioids is limited by severe side effects such asnausea and vomiting, constipation, dizziness, somnolence, respiratorydepression, physical dependence and abuse. Furthermore, it is known thatMOP receptor agonists show only reduced effectiveness under conditionsof chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strongopioids are mediated by activation of classic opioid-receptors withinthe central nervous system. Furthermore, peripheral opioid receptors,when activated, can inhibit transmission of nociceptive signals shown inboth, clinical and animal studies (Gupta et al., 2001; Kalso et al.,2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemicadministration, one approach has been to provide peripherally restrictedopioid receptor ligands that do not easily cross the blood-brain barrierand therefore distribute poorly to the central nervous system (see forinstance WO 2015/192039). Such peripherally acting compounds mightcombine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with boththe NOP receptor and the MOP receptor. Such compounds have for instancebeen described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesicsthat modulate more than one of the opioid receptor subtypes to provideadditive or synergistic analgesia and/or reduced side effects like abuseliability or tolerance.

On the one hand, it would be desirable to provide analgesics thatselectively act on the NOP receptor system but less pronounced on theclassic opioid receptor system, especially MOP receptor system, whereasit would be desirable to distinguish between central nervous activityand peripheral nervous activity. On the other hand, it would bedesirable to provide analgesics that act on the NOP receptor system andalso to a balanced degree on the MOP receptor system, whereas it wouldbe desirable to distinguish between central nervous activity andperipheral nervous activity.

There is a need for medicaments which are effective in the treatment ofpain and which have advantages compared to the compounds of the priorart. Where possible, such medicaments should contain such a small doseof active ingredient that satisfactory pain therapy can be ensuredwithout the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically activecompounds, preferably analgesics that have advantages compared to theprior art.

This object has been achieved by the subject-matter of the patentclaims.

A first aspect of the invention relates to3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivativesaccording to general formula (I)

whereinR¹ and R² independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted; ora 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted;orR¹ and R² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I;preferably with the proviso that R¹ and R² do not simultaneously mean—H;R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 6-14-memberedaryl moiety is optionally connected through —C(═O)—, —C(═O)O—,—C(═O)O—CH₂—, or —S(═O)₂—; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;X means —O—, —S— or —NR⁶—;R⁵ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;in case X means NR⁶, R⁶ means

H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;wherein “mono- or polysubstituted” means that one or more hydrogen atomsare replaced by a substituent independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹,—C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃,═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²²,—NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆, —C(═O)OR²², —NR²³—(CH₂)₁₋₆,—C(═O)NR²¹R²², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²²,—NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹, —S(═O)₂R²¹, —S(═O)₂OR²¹, and—S(═O)₂NR²¹R²²;whereinR²¹, R²² and R²³ independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, and —O—C₁-C₆-alkyl;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²²together with the nitrogen atom to which they are attached form a ringand mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(B)—(CH₂)₂—,wherein R^(B) means —H or —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br and —I;or a physiologically acceptable salt thereof.

Preferably, aryl includes but is not limited to phenyl and naphthyl.Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole,-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,-imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is notlimited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl.Preferably, heterocycloalkyl includes but is not limited to -aziridinyl,-azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,-sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl, and-pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O—or —C(═O)O—CH₂—, said asymmetric group may be arranged in eitherdirection. For example, when R⁴ is connected to the core structurethrough —C(═O)O—, the arrangement may be either R⁴—C(═O)O-core orcore-C(═O)O—R⁴.

In preferred embodiments of the compound according to the invention, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independentlyof one another mean —H, —F, —OH, or —C₁-C₆-alkyl; preferably —H.

In a preferred embodiment of the compound according to the invention, R¹means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹means —H and R² means —CH₃.

In another preferred embodiment of the compound according to theinvention, R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to theinvention, R¹ and R² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—. Preferably, R¹ and R² togetherwith the nitrogen atom to which they are attached form a ring and mean—(CH₂)₃—.

In yet another preferred embodiment,

-   -   R¹ means —H or —CH₃; and    -   R² means a 3-12-membered cycloalkyl moiety, saturated or        unsaturated, unsubstituted; wherein said 3-12-membered        cycloalkyl moiety is connected through —CH₂—, unsubstituted;        preferably —CH₂-cycloalkyl, —CH₂-cyclobutyl or —CH₂-cyclopentyl;        or R² means a 3-12-membered heterocycloalkyl moiety, saturated        or unsaturated, unsubstituted; wherein said 3-12-membered        heterocycloalkyl moiety is connected through —CH₂—,        unsubstituted; preferably —CH₂-oxetanyl or        —CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to theinvention, R³ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted, optionally connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted. In a preferredembodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted.More preferably, R³ means -phenyl unsubstituted, mono- or disubstitutedwith —F, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F. Inanother preferred embodiment, R³ means -benzyl unsubstituted, mono- orpolysubstituted. More preferably, R³ means -benzyl unsubstituted, mono-or disubstituted with —F, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃,preferably —F.

In still another preferred embodiment of the compound according to theinvention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted. Preferably, R³ means -thienyl or -pyridinyl,in each case unsubstituted, mono- or polysubstituted. More preferably,R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in eachcase unsubstituted or monosubstituted with —F, —Cl or —CH₃.

In a preferred embodiment of the compound according to the invention, R⁴means —H.

In another preferred embodiment of the compound according to theinvention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with a substituent selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —OCF₃,—O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀, —CH₃, —C(═O)C₁-C₄-alkyl,—C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)NHC₁—C₄-alkylene-CN, —C(═O)NHC₁—C₄-alkylene-O—C₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂; —S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; orwith —C(═O)NR²¹R²² wherein R²¹ and R²² together with the nitrogen atomto which they are attached form a ring and mean —(CH₂)₃₋₆—,—(CH₂)₂—O—(CH₂)₂—, or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or—C₁-C₆-alkyl; or with —C(═O)NH-3-12-membered cycloalkyl, saturated orunsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I,—CN, or —OH; or with —C(═O)NH-3-12-membered heterocycloalkyl, saturatedor unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I,—CN, or —OH. More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted or monosubstituted with—O—C₁-C₄-alkyl or —C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to theinvention, R⁴ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂—or —CH₂CH₂—. More preferably, R⁴ means a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁴means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means-oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connectedthrough —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment of the compound according to theinvention, R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁴ means -phenyl,unsubstituted, mono- or polysubstituted; wherein said -phenyl isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to theinvention, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said -phenyl is connected through —CH₂— or—CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl,-pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—C₁-C₄-alkyl —O—C₁-C₄-alkyl —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl,or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means —H.

In another preferred embodiment of the compound according to theinvention, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted, mono-or polysubstituted. More preferably, R⁵ means —C₁-C₆-alkyl, linear orbranched, saturated, unsubstituted or monosubstituted with a substituentselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl, S(═O)₂C₁—C₄alkyl, —C(═O)—C₃₋₁₂heterocycloalkyl, —NH—C(═O)—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)₂ andNH—S(═O)₂—C₁-C₄-alkyl.

In still another preferred embodiment of the compound according to theinvention, R⁵ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted, wherein said3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁵ means a3-6-membered cycloalkyl moiety, saturated, unsubstituted, mono- orpolysubstituted, wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated, unsubstituted; more preferably -cyclopropyl, -cyclobutyl,-cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F,—OH, —CN or —C₁-C₄-alkyl, wherein said -cyclopropyl, -cyclobutyl-cyclopentyl or -cyclohexyl is optionally connected through —CH₂— or—CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁵ means a4-6-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted. More preferably, R⁵ means-hetero-cyclobutyl or -tetrahydro-2H-thiopyranyl dioxide, unsubstituted.

In yet another preferred embodiment of the compound according to theinvention, R⁵ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R⁵ means a 5-6-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted, wherein said 5-6-membered heteroaryl moiety isoptionally connected through —CH₂—. More preferably, R⁵ means a5-6-membered heteroaryl moiety, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl,—S(═O)₂C₁-C₄-alkyl and —S—C₁-C₄-alkyl, wherein said 5-6-memberedheteroaryl moiety is optionally connected through —CH₂—. Still morepreferably, R⁵ means -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl,-pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or-pyrimidinyl, in each case unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁—C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, S(═O)C₁-C₄-alkyl,—S(═O)₂C₁-C₄-alkyl and —S—C₁-C₄-alkyl, wherein said -oxazolyl,-isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl,-thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl is optionallyconnected through —CH₂—.

In a further preferred embodiment of the compound according to theinvention, R⁵ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁵means -phenyl, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl,—C(═O)OH, —C(═O)OC₁—C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁—C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl and—S—C₁-C₄-alkyl, wherein said -phenyl is optionally connected through—CH₂—.

In a preferred embodiment of the compound according to the invention, Xmeans NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, Xmeans NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 5-6-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted. More preferably, Xmeans NR⁶ and R⁵ and R⁶ together with the nitrogen atom to which theyare attached form -pyrrolidinyl, -piperidinyl, -piperazinyl,-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or-(methylsulfonyl)piperazinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of ═O, —OH, —CH₂—OH and —C(═O)NH₂,wherein said -pyrrolidinyl, -piperidinyl, piperazinyl, -morpholinyl,-thiomorpholinyl, -thiomorpholinyl dioxide or-(methylsulfonyl)piperazinyl is optionally condensed with an imidazolemoiety, unsubstituted.

In a preferred embodiment of the compound according to the invention R⁵means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀, —H, —O—(CH₂CH₂—O)₁₋₁₀,—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OH,—S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃,—N(CH₃)₂ and NH—S(═O)₂—CH₃;-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted ormonosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl,-cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through—CH₂— or —CH₂CH₂—;-heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,—O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C₁-C₄-alkyl, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,—C(═O)NHCH₃, —C(═O)N(CH₃)₂, ═O, —OH, —SCH₃, —S(═O)CH₃, —S(═O)₂CH₃,unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ andNH—S(═O)₂—CH₃; wherein said -heterocyclobutyl, -heterocyclopentyl, or-heterocyclohexyl is optionally connected through —CH₂— or —CH₂CH₂—;-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,—C(═O)NHCH₃, —C(═O)N(CH₃)₂, —S(═O)CH₃, —S(═O)₂CH₃ and —S—CH₃, whereinsaid -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionallyconnected through —CH₂—; or-phenyl, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,—C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂ CH₃and —S—CH₃, wherein said -phenyl is optionally connected through —CH₂—;in case X means NR⁶, R⁶ means —H or —CH₃;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxideor -(methylsulfonyl)piperazinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, —CH₂—OH,—C(═O)NH₂, and —S(═O)₂CH₃, wherein said -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxideor -(methylsulfonyl)piperazinyl is optionally condensed with animidazole moiety, unsubstituted;

In a preferred embodiment of the compound according to the invention, Xmeans NR⁶ and R⁶ means —H or —C₁-C₆-alkyl, linear or branched, saturatedor unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁶means —H or —CH₃.

In preferred embodiments, the compound according to the invention has astructure according to any of general formulas (II-A) to (VIII-C):

wherein in each caseR¹, R², R³, R⁴, R⁵, R⁶ and X are defined as above,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl;R^(D) means —H or —F;or a physiologically acceptable salt thereof.

Preferably, the substructure of the compounds according to generalformula (I) represented by R⁵, X, R⁹ and R¹⁰, i.e.

or the corresponding substructure of any of above general formulas(II-A) to (VIII-C) has preferably a meaning selected from the groupconsisting of:

In a particularly preferred embodiment of the compound according to theinvention

R¹ means —H or —CH₃;R² means —CH₃, —CH₂CH₃ or —CH₂—C(H)(CH₃)₂;R³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted ormonosubstituted with —F;R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, ═O, —N(CH₃)₂ and —O—CH₃; or-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted ormonosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl,-cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH₂— or—CH₂CH₂—;-oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃,wherein said -oxetanyl is connected through —CH₂— or —CH₂CH₂—;X means —O— or —NR⁶—;R⁵ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H, —O—(CH₂CH₂—O)₁₋₁₀—CH₃,—C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OH,—S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃,—N(CH₃)₂ and NH—S(═O)₂—CH₃;-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted ormonosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl,-cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through—CH₂— or —CH₂CH₂—;-heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H,—O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C₁-C₄-alkyl, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,—C(═O)NHCH₃, —C(═O)N(CH₃)₂, ═O, —OH, —SCH₃, —S(═O)CH₃, —S(═O)₂CH₃,unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃, —N(CH₃)₂ andNH—S(═O)₂—CH₃; wherein said -heterocyclobutyl, -heterocyclopentyl, or-heterocyclohexyl is optionally connected through —CH₂— or —CH₂CH₂—;-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,—C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂CH₃ and —S—CH₃, whereinsaid -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionallyconnected through —CH₂—; or-phenyl, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,—C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂ CH₃and —S—CH₃, wherein said -phenyl is optionally connected through —CH₂—;in case X means NR⁶, R⁶ means —H or —CH₃;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxideor -(methylsulfonyl)piperazinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, —CH₂—OH,—C(═O)NH₂, and —S(═O)₂CH₃, wherein said -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxideor -(methylsulfonyl)piperazinyl is optionally condensed with animidazole moiety, unsubstituted; andR⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

In a particularly preferred embodiment of the compound according to theinvention

R¹ means —H or —CH₃; and/orR² means —CH₃, —CH₂CH₃ or —CH₂—C(H)(CH₃)₂; and/orR³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted;preferably, R³ means phenyl unsubstituted; and/orR⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, ═O, —N(CH₃)₂ and —O—CH₃; or-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted ormonosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl,-cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH₂— or—CH₂CH₂—; preferably, R⁴ means -cyclobutyl, unsubstituted ormonosubstituted with —OH, wherein said -cyclobutyl is connected through—CH₂—; and/orX means —O— or —NR⁶—; and/orR⁵ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H, —O—(CH₂CH₂—O)₁₋₁₀,—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OH,—S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃,—N(CH₃)₂ and NH—S(═O)₂—CH₃; preferably, R⁵ means —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted or monosubstitutedwith —OH;-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted ormonosubstituted with —F, —OH, —CN or —CH₃, wherein said -cyclopropyl,-cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through—CH₂— or —CH₂CH₂—;-heterocyclobutyl, -tetrahydro-2H-thiopyranyl dioxide,—CH₂-heterocyclobutyl or —CH₂-tetrahydro-2H-thiopyranyl dioxide, in eachcase unsubstituted;-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl, ineach case unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,—C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂CH₃and —S—CH₃, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl,-pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or-pyrimidinyl is optionally connected through —CH₂—; preferably, R⁵ means-pyridinyl unsubstituted; or-phenyl, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH,—C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂ CH₃and —S—CH₃, wherein said -phenyl is optionally connected through —CH₂—;and/orin case X means NR⁶, R⁶ means —H or —CH₃;or in case X means NR⁶, R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a -pyrrolidinyl, -piperidinyl,-piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxideor -(methylsulfonyl)piperazinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of ═O, —OH, —CH₂—OH and—C(═O)NH₂, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl,-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or-(methylsulfonyl)piperazinyl is optionally condensed with an imidazolemoiety, unsubstituted; and/orR⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

Preferably, the compound according to the invention is selected from thegroup consisting of

SC_1001 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1002CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acidmethyl ester SC_1003CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamideSC_1004 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamideSC_1005 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamideSC_1006CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl esterSC_1007CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamideSC_1008CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamideSC_1009CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamideSC_1010 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamideSC_1011CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide SC_1012CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide SC_1013CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1014CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide SC_1015CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylicacid amide SC_1016CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamideSC_1017 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamideSC_1018 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamideSC_1019 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamideSC_1020CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1021CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamideSC_1022 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamideSC_1023 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide SC_1024CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamideSC_1025 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1026CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1027CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl esterSC_1028 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide SC_1029CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1030CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1031CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamideSC_1032CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl esterSC_1033 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide SC_1034CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide SC_1035CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide SC_1036CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide SC_1037CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide SC_1038CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide SC_1039CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide SC_1040CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide SC_1041CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide SC_1042CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide SC_1043CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide SC_1044CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide SC_1045CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide SC_1046CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide SC_1047CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide SC_1048CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide SC_1049CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamideSC_1050 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamideSC_1051 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamidc SC_1052CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamideSC_1053 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide SC_1054CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide SC_1055CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamideSC_1056 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide SC_1057CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide SC_1058CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1059CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1060CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1061CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide SC_1062CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamideSC_1063CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1064CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamideSC_1065CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide SC_1066CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_1067CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamideSC_1068 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1069CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamideSC_1070 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamideSC_1072CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1073CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylicacid amide SC_1074CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamideSC_1075CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1076CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acidamide SC_1077CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1078CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1079CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acidamide SC_1080CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1081CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide SC_1082CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide SC_1083CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide SC_1084CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide SC_1085CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamideSC_1086CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamideSC_1087 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide SC_1088CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide SC_1089CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamideSC_1090 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamideSC_1091 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamideSC_1092 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide SC_1093CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide SC_1094CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide SC_1095CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide SC_1096CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide SC_1097CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamideSC_1098 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamideSC_1099 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamideSC_1100 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamideSC_1101 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamideSC_1102 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamideSC_1103 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide SC_1104CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylicacid amide SC_1105CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acidamide SC_1106CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamideSC_1107 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamideSC_1109 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamideSC_1110 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamideSC_1111 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide SC_1112CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide SC_1113CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1114CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1115CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1117CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1118CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamideSC_1119 ClS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamideSC_1120 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamideSC_1121 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1122CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1123CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1124CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1125CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide SC_1126CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamideSC_1127 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamideSC_1128CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1129CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamideSC_1130CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide SC_1131CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1132CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1133CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamideSC_1134CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1135CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamideSC_1136CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1137CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1138CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamideSC_1139CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1140CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamideSC_1141CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1142CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1143CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3yl]-acetyl]amino]-N,N-dimethyl-acetamide SC_1144CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamideSC_1145 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamideSC_1146CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1147CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1148CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide SC_1149CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1150CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamideSC_1151 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide SC_1152CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1154CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1155CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1156CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1157CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1158CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1159CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1160CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1161CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1162CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1163CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1164CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1165CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1166CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1167CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1168CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1169CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1171CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide SC_1172CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1173CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1174CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide SC_1175CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1176CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1177CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1178CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1179CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamideSC_1180 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1181CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamideSC_1182CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1183CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1184CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamideSC_1185 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamideSC_1186 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamideSC_1187 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide SC_1188CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1189CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1190CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1191CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1192CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide SC_1193CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide SC_1195CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1196CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1197CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-cthyl)-acetamide SC_1198CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-cthyl)-acetamide SC_1199CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide SC_1201CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1203CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid amideSC_1204CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide SC_1205CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1206CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1207CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1208CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide SC_1209CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1210CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1211CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1212CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1213CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1214CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1215CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamideSC_1216CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1217CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1218CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamideSC_1219 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamideSC_1220 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamideSC_1222CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide SC_1223CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamideSC_1224 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamideSC_1225 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamideSC_1226 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamideSC_1227 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide SC_1228CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1229CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1230CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1231CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide SC_1232CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide SC_1233CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1234CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide SC_1235CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamideSC_1236 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide SC_1300CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide SC_1301CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1302CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1303CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1304CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1305CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide SC_1306CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide SC_1308CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_1309CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide SC_1310CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1311CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1312CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1313CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_1317CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide SC_1318CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1319CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1320CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1321CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamideSC_1322CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1323CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamideSC_1324CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamideSC_1325CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1326TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1327CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1328CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamideSC_1329TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamideSC_1330CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-acetamide SC_1331CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dioneSC_1332CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide SC_1333CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1334CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide SC_1335CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1336CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide SC_1337CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dioneSC_1338CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide SC_1339CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1340CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide SC_1341CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1342CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1343CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1344CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1345CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamideSC_1346CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester SC_1347CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamideSC_1348CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide SC_1349CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamideSC_1350CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amideSC_1351CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_1352CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1353TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1354TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1355CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_1356CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1357TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1358TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1359CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamideSC_1360CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamideSC_1361CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1362CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amideSC_1363TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide SC_1364TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1365TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1366CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1368CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_1369TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide SC_1370TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1371CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_1372CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-oneand the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can belinear or branched, saturated or unsaturated. Linear saturated alkylincludes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.Examples of branched saturated alkyl include but are not limited toiso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturatedalkyl include but are not limited to vinyl, propenyl, allyl, andpropargyl.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can beunsubstituted, mono- or polysubstituted. Examples of substituted alkylinclude but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₃)₂C(═O)NH₂,and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of saturatedalkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—,—CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—,—CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkyleneinclude but are not limited to —CH═CH—, —C(CH₃)═CH—, —CH═C(CH₃)—,—C(CH₃)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of substituted—C₁-C₆-alkylene- include but are not limited to —CHF—, —CF₂—, —CHOH— and—C(═O)—.

According to the invention, moieties may be connected through—C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to thecore structure of compound according to general formula (I), but may beconnected to the core structure of compound according to general formula(I) or its periphery through a —C₁-C₆-alkylene- linker.

According to the invention, “3-12-membered cycloalkyl moiety” means anon-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to12 ring carbon atoms but no heteroatoms in the ring. Examples ofpreferred saturated 3-12-membered cycloalkyl moieties according to theinvention include but are not limited to cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, anddecaline. Examples of preferred unsaturated 3-12-membered cycloalkylmoiety moieties according to the invention include but are not limitedto cyclopropene, cyclobutene, cyclopentene, cyclopentadiene,cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The3-12-membered cycloalkyl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 6-14-memberedaryl moiety, unsubstituted, mono- or polysubstituted; and/or with a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 3-12-membered heterocycloalkyl moieties includebut are not limited to octahydro-1H-indol, decahydroquinoline,decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, anddecahydro-quinoxalin, which in each case are connected through the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 6-14-membered aryl moieties include but are notlimited to 2,3-dihydro-1H-indene and tetraline, which in each case areconnected through the 3-12-membered cycloalkyl moiety. Examples of3-12-membered cycloalkyl moieties condensed with 5-14-memberedheteroaryl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-memberedcycloalkyl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene- linker. Examples include but are not limited to—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and—CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the3-12-membered cycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered cycloalkylmoieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety”means a non-aromatic, monocyclic, bicyclic or tricyclic moietycomprising 3 to 12 ring atoms, wherein each cycle comprisesindependently of one another 1, 2, 3, 4 or more heteroatomsindependently of one another selected from the group consisting ofnitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) orS(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereasbicyclic or tricyclic systems may share common heteroatom(s). Examplesof preferred saturated 3-12-membered heterocycloalkyl moieties accordingto the invention include but are not limited to aziridin, azetidine,pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine,triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane,tetrahydropyrane, thiirane, thietane, tetra-hydrothiophene, diazepane,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, morpholine, thiomorpholine. Examples of preferredunsaturated 3-12-membered heterocycloalkyl moiety moieties according tothe invention include but are not limited to oxazoline, pyrazoline,imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.The 3-12-membered heterocycloalkyl moiety, which is bonded to thecompound according to the invention, in its periphery may optionally becondensed with a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; and/or with a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered heterocycloalkyl moieties. Examples of 3-12-memberedheterocycloalkyl moieties condensed with 3-12-membered cycloalkylmoieties include but are not limited to octahydro-1H-indol,decahydroquinoline, decahydroisoquinoline,octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which ineach case are connected through the 3-12-membered heterocycloalkylmoiety. An examples of a 3-12-membered heterocycloalkyl moiety condensedwith a 6-14-membered aryl moiety includes but is not limited to1,2,3,4-tetrahydroquinoline, which is connected through the3-12-membered heterocycloalkyl moiety. An example of a 3-12-memberedheterocycloalkyl moiety condensed with a 5-14-membered heteroarylmoieties includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moietymay optionally be connected through —C₁-C₆-alkylene-, i.e. the3-12-membered heterocycloalkyl moiety may not be directly bound to thecompound according to general formula (I) but may be connected theretothrough a —C₁-C₆-alkylene- linker. Said linker may be connected to acarbon ring atom or to a hetero ring atom of the 3-12-memberedheterocycloalkyl moiety. Examples include but are not limited to—CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine,—CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and—CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered heterocycloalkylmoieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-,3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl,3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl,-tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention, “6-14-membered aryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring carbon atoms but no heteroatoms in the ring. Examples of preferred6-14-membered aryl moieties according to the invention include but arenot limited to benzene, naphthalene, anthracen, and phenanthren. The6-14-membered aryl moiety, which is bonded to the compound according tothe invention, in its periphery may optionally be condensed with a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 6-14-membered aryl moieties condensed with 3-12-memberedcycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indeneand tetraline, which in each case are connected through the6-14-membered aryl moiety. An example of a 6-14-membered aryl moietycondensed with a 3-12-membered heterocycloalkyl moiety includes but isnot limited to 1,2,3,4-tetrahydroquinoline, which is connected throughthe 6-14-membered aryl moiety. Examples of 6-14-membered aryl moietiescondensed with 5-14-membered heteroaryl moieties include but are notlimited to quinoline, isoquinoline, phenazine and phenoxacine, which ineach case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionallybe connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered arylmoiety may not be directly bound to the compound according to generalformula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to ahetero ring atom of the 6-14-membered aryl moiety. Examples include butare not limited to —CH₂—C₆H₅, —CH₂CH₂—C₆H₅ and —CH═CH—C₆H₅.

According to the invention, unless expressly stated otherwise, the6-14-membered aryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 6-14-membered aryl moietiesinclude but are not limited to 2-fluorophenyl, 3-fluorophenyl,2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring atoms, wherein each cycle comprises independently of one another 1,2, 3, 4 or more heteroatoms independently of one another selected fromthe group consisting of nitrogen, oxygen and sulfur, whereas theremaining ring atoms are carbon atoms, and whereas bicyclic or tricyclicsystems may share common heteroatom(s). Examples of preferred5-14-membered heteroaryl moieties according to the invention include butare not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine,pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine,1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The5-14-membered heteroaryl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 5-14-membered heteroaryl moieties condensed with3-12-membered cycloalkyl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 5-14-membered heteroaryl moiety. Anexamples of a 5-14-membered heteroaryl moiety condensed with a3-12-membered heterocycloalkyl moiety includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 5-14-membered heteroaryl moiety. Examples of 5-14-memberedheteroaryl moieties condensed with 6-14-membered aryl moieties includebut are not limited to quinoline, isoquinoline, phenazine andphenoxacine, which in each case are connected through the 5-14-memberedheteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 5-14-memberedheteroaryl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene- linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.Examples include but are not limited to —CH₂-oxazole, —CH₂-isoxazole,—CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine,—CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine,—CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the5-14-membered heteroaryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of 5-14-membered heteroaryl moieties includebut are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl,2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl,3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl,4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and2-methoxy-6-pyrazinyl.

Preferably, the compounds according to the invention have a structureaccording to general formula (I′)

wherein R¹ to R⁵, R⁹ to R²⁰, and X are defined as above, or aphysiologically acceptable salt thereof.

In one preferred embodiment, the excess of the cis-isomer so designatedis at least 50% de, more preferably at least 75% de, yet more preferablyat least 90% de, most preferably at least 95% de and in particular atleast 99% de.

Preferably, the compounds according to the invention have a structureaccording to general formula (IX)

whereinR^(C) means —H or —OH;R³ means -phenyl or -3-fluorophenyl;R⁵ means —H, —CH₃, —CH₂CH₂OH, or —CH₂C(═O)NH₂;R⁶ means —H or —CH₃;or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₅—, wherein said ring is unsubstituted orsubstituted with one or two substituents independently of one anotherselected from the group consisting of —CH₃, —OH, —S(═O)₂CH₃ and—C(═O)NH₂;R⁹ and R¹⁰ independently of one another mean —H or —CH₃;or a physiologically acceptable salt thereof.

In a preferred embodiment, the compounds according to the invention arein the form of the free bases.

In another preferred embodiment, the compounds according to theinvention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood asbeing any form of the compound in which it assumes an ionic form or ischarged and is coupled with a counter-ion (a cation or anion) or is insolution. The term is also to be understood as meaning complexes of thecompound with other molecules and ions, in particular complexes whichare associated via ionic interactions. Preferred salts arephysiologically acceptable, in particular physiologically acceptablesalts with anions or acids or also a salt formed with a physiologicallyacceptable acid.

Physiologically acceptable salts with anions or acids are salts of theparticular compound in question with inorganic or organic acids whichare physiologically acceptable, in particular when used in humans and/ormammals. Examples of physiologically acceptable salts of particularacids include but are not limited to salts of hydrochloric acid,sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according tothe invention, wherein at least one atom of the compound is replaced byan isotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium), ³H(tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating apharmacodynamic response from one or more opioid receptors (mu, delta,kappa, NOP/ORL-1) either centrally or peripherally, or both. Thepharmacodynamic response may be attributed to the compound eitherstimulating (agonizing) or inhibiting (antagonizing) the one or morereceptors. Certain compounds according to the invention may antagonizeone opioid receptor, while also agonizing one or more other receptors.Compounds according to the invention having agonist activity may beeither full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to a receptor but produce no regulatory effect, butrather block the binding of ligands to the receptor, are defined as“antagonists”.

In certain embodiments, the compounds according to the invention areagonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or deltaopioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/orKOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOPand/or KOP and/or DOP and/or NOP receptors, and therefore the compoundsaccording to the invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention areagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are agonists of the MOP and/or KOPand/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention areantagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are antagonists of the MOP and/orKOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) agonist activity atone or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) antagonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) agonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) antagonistactivity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the NOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the MOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        DOP receptor;    -   can be regarded as opioid pan agonists, i.e. have agonist        activity at the NOP receptor as well as agonist activity at the        MOP receptor as well as agonist activity at the KOP receptor as        well as agonist activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the KOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the KOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveagonist activity at the MOP receptor, agonist activity at the KOPreceptor, and antagonist activity at the DOP receptor. In someembodiments, preferably with respect to receptors of the peripheralnervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as agonist activity at the NOP        receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as antagonist activity at the NOP        receptor; or    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveantagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have antagonistactivity at the NOP receptor as well as agonist activity at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

For the purpose of the specification, “no significant activity” meansthat the activity (agonist/antagonist) of the given compound at thisreceptor is lower by a factor of 1000 or more compared to its activity(agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according tothe invention as medicaments.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of pain. A further aspect of theinvention relates to a method of treating pain comprising theadministration of a pain alleviating amount of a compound according tothe invention to a subject in need thereof, preferably to a human. Thepain is preferably acute or chronic. The pain is preferably nociceptiveor neuropathic.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of neurodegenerative disorders,neuroinflammatory disorders, neuropsychiatric disorders, and substanceabuse/dependence. A further aspect of the invention relates to a methodof treating any one of the aforementioned disorders, diseases orconditions comprising the administration of a therapeutically effectiveamount of a compound according to the invention to a subject in needthereof, preferably to a human.

Another aspect of the invention relates to a pharmaceutical compositionwhich contains a physiologically acceptable carrier and at least onecompound according to the invention.

Preferably, the composition according to the invention is solid, liquidor pasty; and/or contains the compound according to the invention in anamount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, basedon the total weight of the composition.

The pharmaceutical composition according to the invention can optionallycontain suitable additives and/or auxiliary substances and/or optionallyfurther active ingredients.

Examples of suitable physiologically acceptable carriers, additivesand/or auxiliary substances are fillers, solvents, diluents, coloringsand/or binders. These substances are known to the person skilled in theart (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetikand angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains thecompound according to the invention in an amount of preferably from0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet morepreferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. %and in particular from 2.5 to 60 wt. %, based on the total weight of thepharmaceutical composition.

The pharmaceutical composition according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration.

Another aspect of the invention relates to a pharmaceutical dosage formwhich contains the pharmaceutical composition according to theinvention.

In one preferred embodiment, the pharmaceutical dosage form according tothe invention is produced for administration twice daily, foradministration once daily or for administration less frequently thanonce daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can beadministered, for example, as a liquid dosage form in the form ofinjection solutions, drops or juices, or as a semi-solid dosage form inthe form of granules, tablets, pellets, patches, capsules,plasters/spray-on plasters or aerosols. The choice of auxiliarysubstances etc. and the amounts thereof to be used depend on whether theform of administration is to be administered orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or locally, forexample to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules,granules, drops, juices and syrups are suitable for oral administration,and solutions, suspensions, readily reconstitutable dry preparations andalso sprays are suitable for parenteral, topical and inhalatoryadministration. Compounds according to the invention in a depot, indissolved form or in a plaster, optionally with the addition of agentspromoting penetration through the skin, are suitable percutaneousadministration preparations.

The amount of the compounds according to the invention to beadministered to the patient varies in dependence on the weight of thepatient, on the type of administration, on the indication and on theseverity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg,preferably from 0.001 mg/kg to 10 mg/kg, of at least one compoundaccording to the invention is administered.

Another aspect of the invention relates to a process for the preparationof the compounds according to the invention. Suitable processes for thesynthesis of the compounds according to the invention are known inprinciple to the person skilled in the art.

Preferred synthesis routes are described below:

The compounds according to the invention can be obtained via differentsynthesis routes. Depending on the synthesis route, differentintermediates are prepared and subsequently further reacted.

In a preferred embodiment, the synthesis of the compounds according tothe invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIa):

wherein R¹, R² and R³ are defined as above.

In another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of an intermediate according to generalformula (IIIb):

wherein R¹, R² and R³ are defined as above and PG is a protecting group.

Preferably the protecting group is -p-methoxybenzyl. Therefore, inanother preferred embodiment, the synthesis of the compounds accordingto the invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIc):

wherein R¹, R² and R³ are defined as above.

As already indicated, in general formula (IIIc), the -p-methoxybenzylmoiety represents a protecting group which can be cleaved in the courseof the synthesis route.

In yet another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of

-   -   an intermediate according to general formula (IIIa) and        according to general formula (IIIb); or    -   an intermediate according to general formula (IIIa) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIb) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIa), according        to general formula (IIIb) and according to general formula        (IIIc).

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

EXAMPLES

“RT” means room temperature (23±7° C.), “M” are indications ofconcentration in mol/l, “aq.” means aqueous, “anhydr.” means anhydrous,“sat.” means saturated, “sol.” means solution, “conc.” meansconcentrated.

Further Abbreviations

brine saturated aqueous sodium chloride solutionCC column chromatographycHex cyclohexaneDCM dichloromethane

DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide

EDCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideEt ethylether diethyl etherEE ethyl acetateEtOAc ethyl acetateEtOH ethanolh hour(s)H₂O waterHATUO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateLDA Lithium-di-isoproyl-amidMe methylm/z mass-to-charge ratioMeOH methanolMeCN acetonitrilemin minutesMS mass spectrometryNBS N-bromo-succinimideNEt₃ triethylaminePd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)PE petroleum ether (60-80° C.)RM reaction mixtureRT room temperature T3P2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxidetBME tert-butyl methyl etherTHF tetrahydrofuranTFA trifluoroacetic acidv/v volume to volumew/w weight to weightXantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The yields of the compounds prepared were not optimised. Alltemperatures are uncorrected.

All starting materials, which are not explicitly described, were eithercommercially available (the details of suppliers such as for exampleAcros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge,Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® AvailableChemicals Database of MDL, San Ramon, US or the SciFinder® Database ofthe ACS, Washington D.C., US, respectively, for example) or thesynthesis thereof has already been described precisely in the specialistliterature (experimental guidelines can be found in the Reaxys® Databaseof Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or can be prepared usingthe conventional methods known to the person skilled in the art.

The mixing ratios of solvents or eluents for chromatography arespecified in v/v.

All the intermediate products and exemplary compounds were analyticallycharacterised by mass spectrometry (MS, m/z for [M+H]⁺). In addition¹H-NMR and ¹³C spectroscopy was carried out for all the exemplarycompounds and selected intermediate products.

Remark Regarding Stereochemistry

CIS refers to the relative configuration of compounds described herein,in which both nitrogen atoms are drawn on the same face of thecyclohexane ring as described in the following exemplary structure. Twodepictions are possible:

TRANS refers to compounds, in which both nitrogen atoms are on oppositefaces of the cyclohexane ring as described in the following exemplarystructure. Two depictions are possible:

Synthesis of Intermediates Synthesis of INT-799:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaOH (1.42 g, 35.5 mmol) was added to a solution ofCIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere andthe reaction mixture was stirred at 80° C. for 30 min((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was addedand stirring was continued for 2 days at 80° C. The reaction completionwas monitored by TLC. The reaction mixture was diluted with water (500mL) and extracted with diethyl ether (4×300 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford2.5 g (59%) ofCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

TFA (12 mL) was added toCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70°C. for 6 h. The reaction completion was monitored by LCMS. The reactionmixture was concentrated under reduced pressure. To the residue sat. aq.NaHCO₃ was added (until pH 10) and the organic product was extractedwith DCM (3×150 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (230-400 mesh silica gel; 5% MeOHin DCM as eluent) to afford 500 mg (33%) ofCIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]⁺ 358.2

Synthesis of INT-951:CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

Step 1:1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10min 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was addeddropwise over 10 minutes at 0° C. The reaction mixture was allowed tostir at RT for 3 h, then quenched with water and the organic product wasextracted with ethyl acetate (3×200 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford 5 g (crude) of1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrileas gummy brown liquid. The material was used for the next step withoutfurther purification.

Step 2:1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide

TFA (100 mL) was added to1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile(5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture wasstirred at RT for 2 days. The reaction mixture was concentrated invacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and theorganic product was extracted with dichloromethane (3×150 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 3.5 g (crude) of1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide. The material was used for the next step withoutfurther purification.

Step 3:1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

Thionyl chloride (35 mL) was added to1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide(3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at refluxfor 2 h. The reaction mixture was concentrated in vacuo. To the residuesat. aq. NaHCO₃ was added (until pH 10) and the organic product wasextracted with dichloromethane (3×150 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by column chromatography to afford 1.3 g (34% after threesteps) ofCIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile(INT-951). [M+H]⁺ 367.2.

Synthesis of INT-952:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (10 g, 25 mmol) in THF (500 mL) was added KOtBu (7.1 g, 63mmol) at 50° C. The reaction mixture was heated up to reflux,cyclobutylmethylbromide (11.3 g, 76 mmol) was added in one portion, andstirring was continued at reflux for 12 h. KOtBu (7.1 g) andcyclobutylmethylbromide (11.3 g) were added again. The reaction mixturewas allowed to stir another 2 h at reflux, then cooled to RT, dilutedwith water (150 mL) and the layers partitioned. The aqueous layer wasextracted with EtOAc (3×300 mL). The combined organic layers were driedover Na₂SO₄ and then concentrated in vacuo. The residue was filteredthrough a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture. Thefiltrate was concentrated in vacuo and the resulting solid wasrecrystallized from hot ethanol to yield 7.8 g ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952). [M+H]⁺ 461.3.

Synthesis of INT-953:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

To a stirred solution of3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60%dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirredfor 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwiseand stirring was continued for 50 h. TLC analysis showed completeconsumption of the starting material. The reaction mixture was quenchedwith sat. aq. NH₄Cl (50 ml) and extracted with EtOAc (3×200 ml). Thecombined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. The resulting residue was purified columnchromatography (neutral aluminum oxide, EtOAc—petroleum ether (2:8)) togive1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4);R_(f)=0.48.

Step 2:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione

To a stirred solution of1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. Thereaction mixture was warmed up to RT and stirred for 16 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was quenched with sat. aq. NaHCO₃ (30 ml) and extracted withEtOAc (3×50 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether(1:3)→(3:7)) to give1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4);R_(f)=0.40.

Step 3:1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol)and MeOH/H₂O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and thereaction mixture was stirred for 10 min at 0° C. (ice bath). A solutionof1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were addedand the reaction mixture was stirred at 45° C. for 20 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml),the combined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure to give1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1);R_(f)=0.45. The product was used for the next step without additionalpurification.

Step 4:CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, 2.81 mmol) was cooled in an ice bath (˜0° C.) and a solution ofphenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.-5°C. The ice bath was removed and the reaction mixture was stirred for 30min, then diluted with sat. aq. NH₄Cl (25 ml) and extracted with EtOAc(4×30 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure to give pale yellow viscous oil.This residue was purified by column chromatography (silica gel, 230-400mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to giveCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1); R_(f)=0.6

Step 5:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containingCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(130 mg, 0.25 mmol) was cooled in an ice bath and a mixture ofTFA/CH₂C₁₂ (2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. Thereaction mixture was warmed to RT and stirred for 20 h, then quenchedwith methanolic NH₃ (10 ml, ˜10% in MeOH) and concentrated under reducedpressure to give pale yellow viscous oil. This residue was purifiedtwice by column chromatography (silica gel, 230-400 mesh, eluent:MeOH—CHCl₃ (1:99)→(2:98)) to giveCIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl₃ (5:95);R_(f) ⁼0.25; [M+H]⁺ 384.3

Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

KOtBu (57.0 g, 508.4 mmol) was added to the solution of2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate(89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h atRT. The reaction mixture was quenched with sat. aq. NH₄Cl and extractedwith EtOAc (2×500 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 68.0g (60%; crude) of ethyl5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid(TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).

Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate(68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacialacetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to100° C. for 16 h. All volatiles were evaporated under reduced pressure.The residue was diluted with sat. aq. NaHCO₃ and extracted with ethylacetate (3×300 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 44.0g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as abrown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45).[M+H]⁺ 201.1

Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958)(44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h usingDean Stark apparatus. All volatiles were evaporated under reducedpressure. The residue was diluted with sat. aq. NaHCO₃ and extractedwith ethyl acetate (3×300 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford 45.0 g (85%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a lightbrown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf:0.55).

Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide

Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H₂O₂ (210.0 mL,1844.2 mmol) were added to the solution of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g,184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture wasstirred at RT for 14 h. The reaction mixture was diluted with water (1.5L) and stirred for 1 h. The precipitated solid was separated byfiltration, washed with water, petroleum ether and dried under reducedpressure to get 32.0 g (66%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a whitesolid. (TLC system: 10% MeOH in DCM Rf: 0.35).

Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate

A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide(25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL,477.09 mmol) and KF—Al₂O₃ (125.0 g) in methanol (500 mL) was heated to80° C. for 16 h. The reaction mixture was filtered through celite andthe solid residue was washed with methanol. The combined filtrate wasconcentrated under reduced pressure. The residue was diluted with waterand extracted with ethyl acetate (3×500 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford 18.0 g (66%) of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brownsolid. (TLC system: 5% MeOH in DCM R_(f): 0.52.)

Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine

A suspension of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. Thereaction mixture was filtered through celite pad, the solid residue waswashed with water and the combined filtrate was extracted with EtOAc(4×200 mL). The combined organic layer washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to afford 12.5 g (88%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brownsemi-solid. (TLC system: 5% MeOH in DCM R_(f): 0.22.).

Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to asolution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g,53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) inacetonitrile (130 mL) at 0° C. The reaction mixture was warmed up toroom temperature and stirred for 16 h. The reaction mixture was quenchedwith sat. aq. NH₄Cl and concentrated under reduced pressure. The residuewas dissolved in water and extracted with EtOAc (3×200 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to afford 10.5 g (72%) of4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a lightbrown solid. (TLC system: 5% MeOH in DCM R_(f): 0.32.). [M+H]⁺ 219.1

Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solutionof 1,4-dioxaspiro[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) atRT under argon atmosphere. The solution was stirred for 10 min and 40 wt% aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) weresequentially added. The reaction mixture was stirred for 48 h at RT,then diluted with water (100 mL) and extracted with EtOAc (2×200 mL).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 44 g of8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as awhite solid.

Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine

8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167mol) in THF (350 mL) was added to the solution of 3M phenylmagnesiumbromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. underargon atmosphere. The reaction mixture was stirred for 4 h at -10° C. to0° C. and then at RT for 18 h. The reaction completion was monitored byTLC. The reaction mixture was cooled to 0° C., diluted with sat. aq.NH₄Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 60 g of, NN-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]-decan-8-amine as a liquid.

Step 3: 4-(dimethylamino)-4-phenylcyclohexanone

A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h andthen at RT for 18 h. The reaction completion was monitored by TLC. Thereaction mixture was extracted with DCM (2×150 mL). The aqueous layerwas basified to pH 10 with solid NaOH and extracted with ethyl acetate(2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The solid residue was washedwith hexane and dried in vacuo to afford 7 g of4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps)as a brown solid. [M+H]⁺ 218.1

Synthesis of INT-966:3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4{circumflex over( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

KCN (93.8 g, 1441.6 mmol) and (NH₄)₂CO₃ (271.8 g, 1729.9 mmol) wereadded to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961mmol) in MeOH:H₂O (1:1 v/v) (1.92 L) at RT under argon atmosphere. Thereaction mixture was stirred at 60° C. for 16 h. The reaction completionwas monitored by TLC. The reaction mixture was cooled to 0° C., theprecipitated solid was filtered off and dried in vacuo to afford 120 g(55%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione. The filtratewas extracted with DCM (2×1.5 L). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordadditional 30 g (14%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (TLCsystem: 10% Methanol in DCM; Rf: 0.4).

Step 2:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}] tetradecane-1,3-dione

Cs₂CO₃ (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g,663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reactionmixture was stirred for 30 min A solution of p-methoxybenzyl bromide (96mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48h. The reaction completion was monitored by TLC. The reaction mixturewas quenched with sat. aq. NH₄Cl (1.0 L) and the organic product wasextracted with EtOAc (2×1.5 L). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was washed with diethyl ether and pentane and dried underreduced pressure to afford 151 g (65%) of2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione as an offwhite solid (TLC system: 10% MeOH in DCM; Rf: 0.6).

Step 3:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}] tetradecan-3-one

AlCl₃ (144.3 g, 1082.6 mmol) was added to a solution of LiAlH₄ (2M inTHF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argonatmosphere and the resulting mixture was stirred at RT for 1 h.2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (150 g,433.05 mmol) was added at 0° C. The reaction mixture was stirred at RTfor 16 h. The reaction completion was monitored by TLC. The reactionmixture was cooled to 0° C., quenched with sat. aq. NaHCO₃(500 mL) andfiltered through celite pad. The filtrate was extracted with EtOAc(2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo to afford 120 g (84%) of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one as an off-whitesolid. (TLC system: 10% MeOH in DCM, Rf: 0.5).

Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

A solution of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflexover ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one (120 g, 361.03mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 h and then at RTfor 18 h. The reaction completion was monitored by TLC. The reactionmixture was extracted with DCM (2×2.0 L). The aqueous layer was basifiedto pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0 L).Combined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The solid residue was washed withhexane and dried in vacuo to afford 90 g of3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4)[M+H]⁺ 289.11.

Synthesis of INT-971:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-968) was converted intoCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

TFA (0.2 mL) was added to the solution ofCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one(300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 3 h. The reaction completion was monitored by TLC.The reaction mixture was quenched with sat. aq. NaHCO₃ and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification of the residue by preparative TLC (3% MeOH in DCMas mobile phase) yielded 50 mg (18%) ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20)[M+H]⁺ 478.3

Synthesis of INT-974:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solutionof 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argonatmosphere. The solution was stirred for 15 min and 40 wt % aq.dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentiallyadded. The reaction mixture was stirred for 48 h and the completion ofthe reaction was monitored by NMR. The reaction mixture was diluted withwater (1.0 L) and the organic product was extracted with ethyl acetate(2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford 90 g (85%) of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrileas an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf:0.35, 0.30).

Step 2:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) wasadded dropwise to a solution of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. Thereaction mixture was stirred for 16 h at RT. The reaction completion wasmonitored by TLC. The reaction mixture was cooled to 0° C., quenchedwith sat. aq. NH₄Cl (200 mL) and the organic product was extracted withEtOAc (2×200 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The reaction was carriedout in 4 batches (15 g×2 and 5 g×2) and the batches were combined forpurification. Purification of the crude product by flash columnchromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol inDCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%)ofCIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presenceof ammonia; Rf: 0.1). [M+H]⁺ 412.2

Synthesis of INT-975:CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reactionmixture was stirred for 30 min 4-Methoxybenzyl bromide (4.23 mL, 29.30mmol) was added and stirring was continued at RT for 4 h. The reactioncompletion was monitored by TLC. The reaction mixture was diluted withsat. aq. NH₄Cl (150 mL) and the organic product was extracted with EtOAc(2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo. The reaction was carried out in 2 batches (8g×2) and the batches were combined for purification. Purification of thecrude product by flash column chromatography on silica gel (0-10%methanol in DCM) and subsequently by washing with pentane yielded 11 g(47%) ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) as a white solid. [M+H]⁺ 394.2

Synthesis of INT-976:CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2g, 9.22 mmol) was suspended in 40 mL EtOH/H₂O (1:1 v/v) at RT underargon atmosphere. (NH₄)₂CO₃ (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22mmol) were added. The reaction mixture was stirred at 60° C. for 18 h.The reaction mixture was cooled to 0° C. and diluted with ice-water andfiltered through a glass filter. The solid residue was dried underreduced pressure to afford8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g,86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf:0.25).

Step 2: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one

LiAlH₄ (2M in THF) (70 mL, 139.4 mmol) was added to the solution of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g,34.8 mmol) in THF/Et₂O (2:1 v/v) (400 mL) at 0° C. under argonatmosphere. The reaction mixture was stirred for 4 h at 60° C. Thereaction completion was monitored by TLC. The reaction mixture wascooled to 0° C., quenched with saturated Na₂SO₄ solution (100 mL) andfiltered through Celite pad. The filtrate was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford 5.7 g (59%) of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one as an offwhite solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).

Step 3: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of CIS- andTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g,29.30 mmol) was purified by preparative chiral SFC (column: ChiralcelAS-H, 60% CO₂, 40% (0,5% DEA in MeOH)) to get 5 g ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) asa white solid. [M+H]⁺ 274.2.

Synthesis of INT-977:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt

Step 1:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester

A solution ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. andtreated with LDA solution (2M in THF/heptane/ether, 25.4 mL, 50.8 mmol).The resulting mixture was was allowed to warm up to RT over 30 min. Thesolution was then cooled to 0° C. again and tert-butyl-bromoacetate(5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RTfor 16 h, quenched with water and extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated innerreduced pressure. Purification of the residue by column chromatographyon silica gel providedCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (4.4 g).

Step 2:cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid trifluoroacetic acid salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) andheated to reflux overnight. After cooling to RT all volatiles areremoved in vacuo. The residue was taken up in THF (1 mL) and addeddropwise to diethyl ether (20 mL). The resulting precipitate wasfiltered off and dried under reduced pressure to giveCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a whitesolid. [M+H]⁺ 332.2

Synthesis of INT-978:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) wasdissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol),dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) weresequentially added. The reaction mixture was stirred at RT overnight,then diluted with 1 M aq. Na₂CO₃ (5 mL). The aqueous layer was extractedwith DCM (3×5 mL), the combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel to yieldCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide(INT-978) (39 mg) as a white solid. [M+H]⁺ 359.2

Synthesis of INT-982:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-[(1-methylcyclobutyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RTfor 10 min.CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for15 min 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) wasadded at 0° C. The reaction mixture was heated to 60° C. for 16 h. Aftercooling down to RT, water (100 mL) was added and the mixture wasextracted with DCM (3×150 mL). The combined organic layers were washedwith water (70 mL), brine (100 mL), dried over Na₂SO₄ and concentratedunder reduced pressure. Purification of the residue by columnchromatography on silica gel providedCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(6.5 g) as a light yellow solid.

Step 2:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution ofCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and theresulting mixture was stirred at RT for 16 h. The reaction mixture wasconcentrated under reduced pressure. The residue was taken up in DCM(100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH 10. Theorganic layer was separated and washed with brine (40 mL), dried overMgSO₄, filtered and concentrated under reduced pressure. Crystallizationof the residue from EtOAc providedCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-982) (3.41 g) as an off-white solid. [M+H]⁺ 356.3

Synthesis of INT-984:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) was converted intoCIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted intoCIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-984).

Synthesis of INT-986:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. Thereaction mixture was basified with 2N aq. NaOH to pH-10 and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL)and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with5N aq. NaOH to pH-10 and extracted with DCM (3×10 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuoto give 3.5 g (crude) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneas semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.60.).

Step 2:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to thesolution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) andacetic acid (0.5 mL) in methanol (20 mL). The reaction mixture wasstirred at RT for 3 h, then quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (3×50 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g(62%) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneas a solid. (TLC system: 50% EtOAc in Pet. Ether; Rf: 0.65).

Step 3:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986)

Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia(˜25 mL) at -78° C. The resulting mixture was stirred for 10 min at −78°C. A solution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reactionmixture was stirred for 15 min, then quenched with sat. aq. NH₄C₁,warmed to RT and stirred for 1 h. The organic product was extracted withDCM (3×50 mL). The combined organic layer was washed with water, brineand concentrated under reduced pressure to afford 1.30 g (72%) ofCIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f):0.15.). [M+H]⁺ 356.3

Synthesis of INT-987:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method as described for INT-982 step 2CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952) was converted intoCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987).

Synthesis of INT-988:CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL),stirred for 10 minutes,8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture wasstirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). Theresulting mixture was stirred overnight at 50° C. The reaction mixturewas quenched with water and extracted with DCM (3×20 mL). The combinedorganic phases were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue (283 mg yellow oil) waspurified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to96/4) to give8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one163 mg (66%).

Step 2:CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-988)

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted intoCIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-988). Mass: m/z 386.3 (M+H)⁺.

Synthesis of INT-992:CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid

CIS-8-Dimethylamino-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-241) (0.9 g, 2.73 mmol) was added to a solution of NaH (60 wt % inmineral oil, 1.64 g, 41.03 mmol) in DMF (20 mL) at RT. The reactionmixture was stirred at RT for 15 min, then cooled to 0° C. and ethyl2-bromoacetate (4.56 g, 27.35 mmol) was added dropwise. The resultingmixture was stirred at RT for 2 days. The reaction completion wasmonitored by TLC. The reaction mixture was quenched with water andconcentrated under reduced pressure. The residue was diluted with smallamount of water and acidified by acetic acid. The resulting mixture wasconcentrated under reduced pressure again. The crude product waspurified by silica gel flash chromatography using 230-400 mesh (25 vol %MeOH in DCM) to afford 1.1 g ofCIS-2-[8-dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid (INT-992) as a solid. [M+H]⁺ 388.3

Synthesis of INT-994:CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid

Step 1: ethyl2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3yl)acetate

KOtBu (1M in THF) (54.90 mL, 54.95 mmol) was added to a solution ofCIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)(10 g, 36.63 mmol) in THF (950 mL) under argon atmosphere at 0° C. andthe reaction mixture was stirred for 15 min A solution of ethylbromoacetate (5.06 mL, 43.96 mmol) in THF (50 mL) was added. Thereaction mixture was warmed up to RT and stirred for 48 h. The reactioncompletion was monitored by TLC. Solvent was evaporated under reducedpressure and the crude product was purified by column chromatography toyield the desired product in 2 fractions: fraction 1: 2.2 g ethyl2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(68% pure according to LCMS) as an off-white solid and Fraction 2: 3.2 gof ethyl2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(32% pure according to LCMS) as well as 1.1 g of unreacted startingmaterial. Fraction 1 was used further without additional purification.

Step 2:2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid

A mixture ofethyl-2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(68% pure, 2.2 g, 6.128 mmol) and powdered NaOH (981 mg, 24.513 mmol) intoluene (40 mL) was stirred at 80° C. for 3 h under argon atmosphere.Ester hydrolysis was monitored by LCMS. Toluene was evaporated underreduced pressure and the resulting crude product (2.4 g) was furtherpurified by reverse phase prep. HPLC to yield 0.93 g of2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid.

Step 3:2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid

To a solution of2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid (1.5 g, 4.532 mmol) in toluene (45 mL) was added in one portionpowdered NaOH (725.08 mg, 18.127 mmol) under argon atmosphere at RT. Thereaction mixture was stirred at 80° C. for 4 h. Toluene was evaporatedunder reduced pressure to get the residue which was dissolved in DMSO(45 mL) under argon atmosphere. The solution was stirred at 55° C. for 1h. To the reaction mixture was added dropwise a solution of1-oxaspiro[2.3]hexane (1.144 g, 13.596 mmol) in DMSO (12 mL) via syringepump (flow rate 10 mL/h). The reaction mixture was stirred at 55° C. for65 h. The reaction progress was monitored by LCMS. DMSO was evaporatedin vacuo. The residue was dissolved in water (50 mL), cooled to 0° C.and pH was adjusted to 3-4 with acetic acid. The resulting mixture wasconcentrated under reduced pressure and the crude product was purifiedby column chromatography (elution with 8-10% MeOH in DCM) to yield 750mg (78%) of2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid (INT-994) as an off-white solid. [M+H]⁺ 416.2

Synthesis of INT-998:CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid; 2,2,2-trifluoro-acetic acid salt

Step 1: CIS-tert-butyl2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate

CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-982) (2.8 g, 7.9 mmol) was dissolved in THF (110 mL) and thesolution was cooled to 0° C. Lithium diisopropylamide solution inTHF/heptane/ethylbenzene (2M, 16 mL) was added dropwise. The reactionmixture was stirred for 30 min and t-butyl-bromoacetate was addeddropwise at the same temperature. The reaction mixture was concentratedin vacuo, water was added and the resulting mixture was extracted withDCM (3×250 mL). The combined organic layers were dried over Na₂SO₄,concentrated in vacuo and the residue was purified by flashchromatography to yield CIS-tert-butyl2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate(1670 mg) as a white solid.

Step 2:CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid; 2,2,2-trifluoro-acetic acid salt

CIS-tert-butyl2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]decan-3-yl]acetat(2250 mg, 4.8 mmol) was treated with TFA (18 mL) at RT. After stirringfor 10 min, all volatiles were removed in vacuo. The residue wastriturated with diethyl ether (30 mL) using ultrasonic bath, the solidrest was dried under reduced pressure to yield CIS-2-[8-dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid; 2,2,2-trifluoro-acetic acid salt (INT-998) (2.2 g) as a brownsolid. [M+H]⁺ 413.3

Synthesis of INT-1008:CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (INT-1004)

A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0eq.) and 2M solution of EtNH₂ in THF (200 ml, 2.5 eq. 400.64 mmol) inEtOH (30 mL) was stirred at RT for 48 h. The reaction mixture wasconcentrated under argon atmosphere. The residue was diluted with ether(60 mL) and added to the freshly prepared PhLi solution [prepared byaddition of 2.5M n-BuLi in THF (70.5 mL, 1.1 eq. 176.27 mmol) to asolution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100mL) at −30° C. and stirred at RT for 1 h] at RT. The reaction mixturewas stirred at RT for 1.5 h, then cooled down to 0° C. and quenched withsat. aq. NH₄Cl (100 mL). The resulting mixture was extracted with EtOAc(2×750 mL), combined organic extracts were washed with water (3×350 mL),brine (300 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was dissolved in ethylmethyl ketone (100 mL)and TMSCl (37.5 mL) was added at 0° C. The reaction mixture was stirredat RT for 16 h, the precipitate formed was filtered off and washed withacetone and THF to giveethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as anoff-white solid. This reaction was done in 2 batches of 25 g scale andthe yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575mmol). LCMS: m/z 262.2 (M+H)⁺.

Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)

To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was addedconc. HCl (62.5 mL) at 0° C. and the reaction mixture was stirred at RTfor 16 h. The reaction mixture was basified with 1N aq. NaOH to pH ˜14at 0° C. and extracted with DCM (2×750 mL). Organic layer was washedwith water (400 mL), brine (400 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanonewhich was used in the next step without further purification. Thisreaction was carried out in another batch of 15.1 g scale and yield isgiven for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).

Step 4: mixture of CIS- andTRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(INT-1006 and INT-1007)

To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol,1.0 eq.) in EtOH (250 mL) and water (200 mL) was added (NH₄)₂CO₃ (18.8g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for15 min KCN (5.09 g, 78.341 mmol, 1.0 eq.) was and the resulting mixturewas stirred at 60° C. for 18 h. The reaction mixture was cooled to RT,the precipitate was filtered off, washed with water (250 mL), EtOH (300mL), hexane (200 mL) and dried under reduced pressure to yield CIS- andTRANS-mixture 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296mmol). LC-MS: m/z [M+1]⁺=288.2.

Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(INT-1006)

To a solution of cis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) inMeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric acid inMeOH (25 mL). The resulting mixture was stirred at RT for 2 h and thenkept in refrigerator for 16 h. The solid material was filtered off andwashed with MeOH/DCM (1:5, 50 ml) to get8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate (7.5g) as a white solid. The solid was suspended in sat. aq. NaHCO₃(pH-8)and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml).Combined organic extracts were washed with water (300 ml), brine (300ml) and dried over anhydrous Na₂SO₄. The solvent was evaporated underreduced pressure and the residue was triturated with 20% DCM-hexane toafford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione asa white solid. This step was done in 2 batches (12 g & 2.4 g) and yieldis given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol).LC-MS: m/z [M+1]⁺=288.0.

Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1008)

To a slurry of LiAlH₄ (793 mg, 20.905 mmol, 3.0 eq.) in THF (15 mL) wasadded a suspension ofcis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g,6.968 mmol, 1.0 eq.) in THF (60 mL) at 0° C. and the reaction mixturewas stirred at 65° C. for 16 h. The resulting mixture was cooled to 0°C., quenched with sat. aq. Na₂SO₄ (20 ml), stirred at RT for 1 h andfiltered through celite. The celite layer was washed with 15% MeOH-DCM(500 ml). The combined filtrate was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting crude product wastriturated with 15% DCM-Hexane to affordCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)(1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol).LC-MS: m/z [M+H]⁺=274.2.

Synthesis of INT-1019:CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid hydrochloride

Step 1: tert-butylCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

The solution ofCIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-799) (1.8 g, 5.042 mmol) in THF (40 mL) was cooled down to 0° C.and KOtBu (1 M in THF, 5.55 mL, 5.546 mmol) was added. The resultingmixture was stirred for 10 min followed by the dropwise addition oftert-butyl bromoacetate (1.081 g, 5.546 mmol). The ice bath was removedand the reaction mixture was stirred for 2 h, then quenched with sat.aq. NH₄Cl (40 mL) and extracted with EtOAc (2×80 mL). The combinedorganic extracts were dried over anhydr. Na₂SO₄ and concentrated underreduced pressure. Crude product was purified by column chromatography(silica gel 100-200 mesh, 0-4% MeOH in DCM as eluent) to afford 1.7 g oftert-butylCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetateas an off white solid.

Step 2:CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid hydrochloride

4N HCl in dioxane (30 mL) was added to the solution of tert-butylCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(1.7 g, 3.609 mmol) in 1,4 dioxane (10 mL). The resulting mixture wasstirred at RT for 16 h and then concentrated under reduced pressure toafford 1.5 g ofCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid hydrochloride (INT-1019) as a hygroscopic solid. TLC R_(f) (10%MeOH in DCM)=0.2. LC-MS: m/z [M+H]⁺=416.3.

Synthesis of INT-1020: sodiumCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

Step 1: tert-butylCIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

To the suspension of tert-butylCIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(INT-1018) (0.5 g, 1.74 mmol) in DMF (11 mL) was added portionwisesodium hydride (60% in mineral oil, 70 mg, 1.74 mmol, 1 equiv.). Thereaction mixture was stirred until the evolution of hydrogen was overand a clear solution was formed (ca. 40 min). Tert-butyl bromoacetate(257 μL, 1.74 mmol, 1 equiv.) was added, the reaction mixture wasstirred at RT overnight, quenched with ca. 40 mL water and stirred for 2h. The precipitate was filtered off, washed with water, hexane and driedunder reduced pressure to give tert-butylCIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(653 mg, 93%) which was used further without additional purification.LC-MS: m/z [M+H]⁺=402.2.

Step 2: sodiumCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(INT-1020)

Sodium hydroxide (135 mg, 3.37 mmol, 4 equiv.) was suspended in dimethylsulfoxide (1.8 mL, 25.26 mmol, 30 equiv.) and the mixture was stirred atRT for 10 min Tert-butylCIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(338 mg, 0.84 mmol, 1 equiv.) was added, the reaction mixture wasstirred 5 min at RT and then heated up to 50° C.[1-[Tert-butyl(dimethyl)silyl]oxycyclobutyl]methyl4-methylbenzenesulfonate (936 mg, 2.53 mmol, 3 equiv.) was added and thereaction mixture was stirred at 60° C. for 3 days. The resulting mixturewas cooled down to RT, diluted with water (5 mL), extracted with EtOAc(1×10 mL) and the aqueous phase was concentrated under reduced pressureto give crude sodiumCIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate(INT-1020) (473 mg) which was used in the next step without furtherpurification. LC-MS: m/z [M+H]+=452.2.

Synthesis of INT-1026:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) atRT and the reaction mixture was stirred at RT for 18 h. The reactionmixture was cooled to 0° C. and quenched by dropwise addition of sat.aq. NaHCO₃(500 mL) over a period of 30 min. The organic product wasextracted with EtOAc (3×100 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 10 g(crude) of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide asa white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2:2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwiseto a solution of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. Thereaction mixture was stirred for 2 h at −10° C. to 0° C. The reactioncompletion was monitored by TLC. The reaction mixture was quenched withsat. aq. NH₄Cl (50 mL) at 0° C. and the organic product was extractedwith EtOAc (3×100 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate inhexane) to yield 6.0 g (46%) of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamideas a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride

2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added toa solution of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide(6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The reaction mixture was concentrated in vacuo.The residue was washed with diethyl ether to yield 3 g (crude) of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid(TLC system: 5% MeOH in DCM; Rf: 0.10).

Step 4:8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine

Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo at 30° C. and to the residue sat. aq. NaHCO₃ was added. Theorganic product was extracted with DCM (3×30 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and solvent was concentratedunder reduced pressure to get 3 g (crude) of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).

Step 5:N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)

Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo and to the residue sat. aq. NaHCO₃ was added. The organic productwas extracted with DCM (3×30 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and solvent was concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) ofN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).

Step 6:4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone

5% sulfuric acid in water (25 mL) was added toN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RTfor 24 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (2×50 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo toafford 2.0 g (crude) of4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as athick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7:8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone(1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H₂O (1:1 v/v) at RTunder argon atmosphere. (NH₄)₂CO₃ (1.9 g, 13.05 mmol) and KCN (0.34 g,5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16h. The reaction mixture was diluted with ice-water and the organicproduct was extracted with DCM (2×50 mL). The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacuo to give 1.0 g(crude) of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dioneas a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

Diastereomeric mixture of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(1.0 g) was separated by reverse phase preparative HPLC to afford 400 mgof isomer 1(CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 60 mg of isomer 2(TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 300 mg of mixture of both isomers. Reverse phase preparative HPLCconditions: mobile phase: 10 mM ammonium bicarbonate inH₂O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 μm, gradient (T/B %):0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min,diluent: mobile phase+THF.

Step 9:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026)

LiAlH₄ (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(isomer-1) (0.4 g, 1.12 mmol) in THF:Et₂O (2:1 v/v, 15 mL) at 0° C.under argon atmosphere. The reaction mixture was stirred at 65° C. for16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄(1000 mL) and filtered through celite pad. The filtrate was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) toyield 0.3 g (78%) ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf:0.2). LC-MS: m/z [M+1]⁺=344.2.

Synthesis of INT-1031:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-952CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) was converted intoCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 21-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-onewas converted into1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1031).

Synthesis of INT-1032:CIS-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]aceticacid trifluoroacetate

In analogy to the method described for INT-998 step 22-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid tert-butyl ester (SC 1346) was converted into2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]aceticacid trifluoroacetate (INT-10322).

Synthesis of INT-1034:CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid

Step 1:CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-aceticacid tert-butyl ester

In analogy to the method described for INT-988 Step 1CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-967)was converted intoCIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (INT-1033). LC-MS: m/z [M+H]⁺=388.3

Step 2:CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-aceticacid tert-butyl ester

To a suspension ofCIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid tert-butyl ester (INT-1033) (8.1 g, 20.90 mmol, 1.0 eq.) in DMF(300 mL) was added NaH (603 mg, 25.11 mmol, 1.2 eq.) at RT and thereaction mixture was stirred for 40 min Trimethylsilylethoxymethylchloride (SEMCl) was added (4.06 ml, 23.02 mmol, 1.1 eq). The resultingmixture was stirred at RT for 16 h, then diluted with ice-water (100 mL)and extracted with ethyl acetate (2×500 mL). The combined organic layerwas washed with water (150 mL), brine (200 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting crude product waspurified by column chromatography (silica gel, 30% ethyl acetate/hexane)to yieldCIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-aceticacid tert-butyl ester (4.0 g, 7.736 mmol, 37%) as a light yellow densesticky liquid. LC-MS: m/z [M+H]⁺=518.3

Step 3:CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-aceticacid tert-butyl ester

In analogy to the method described for INT-986 Step 1CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester was converted intoCIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-aceticacid tert-butyl ester. LC-MS: m/z [M+H]⁺=504.2

Step 4:CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid (INT-1034)

To a solution ofCIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-aceticacid tert-butyl ester (1.6 g, 3.180 mmol, 1.0 eq.) in MeOH (48 mL) wasadded 2N aq. HCl (48 mL) and the mixture was stirred at RT for 16 h. Thereaction mixture concentrated under reduced pressure, diluted with MeOH(40 mL), basified with 1M aq. LiOH (pH-12) and stirred at RT for 16 h.The reaction mixture was concentrated under reduced pressure andacidified to pH˜6 with aq. NaHSO₄. The reaction mixture was extractedwith 20% MeOH/DCM (5×200 ml). The combined organic layer was dried overanhydr. Na₂SO₄ and concentrated under reduced pressure to yieldCIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid (INT-1034) (850 mg, 0.681 mmol, 84%) as an off white solid. Theproduct was used in the next step without further purification. LC-MS:m/z [M+H]⁺=318.2

Synthesis of INT-1035:CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid

Step 1:CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid oxetan-3-ylmethyl ester

In analogy to the method described for INT-986 Step 1CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid tert-butyl ester (INT-1033) was converted intoCIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid oxetan-3-ylmethyl ester.

Step 2:CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid (INT-1035) Synthesis of INT-1037:8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400mL) and the suspension was cooled to 0° C.8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg,0,261 mmol) (step 1 of INT-965) was added portionwise at 0° C. Thereaction mixture was stirred 1.5 h at 0° C., then overnight at RT andthen 2 h at 40° C. The reaction mixture was cooled down to 0° C.,quenched carefully with sat. aq. Na₂SO₄, EtOAc (400 mL) was added andthe resulting mixture was stirred for 2 h and then left without stirringfor 2 h at RT. The precipitate was filtered off and washed with EtOAcand MeOH. The resulting solid residue was suspended in methanol andstirred at RT overnight. The precipitate was filtered off and disposed.The filtrate was concentrated under reduced pressure, the residue wassuspended thoroughly in water (50 mL) at 40° C., the precipitate wasfiltered off and dried under reduced pressure to yield9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflexover ( )}{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2 (M+H)⁺.

Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione

In analogy to the method described for INT-1003 step 39,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflexover ( )}{5}]tetradecan-3-one was treated with conc. aq. HCl to beconverted into 1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1(M+H)⁺.

Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037)

In analogy to the method described for INT-965 step 11,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine andpotassium cyanide to be converted into8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037). Mass: m/z 223.2 (M+H)⁺.

Synthesis of INT-1038:CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

To the suspension of8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1Mbromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and thereaction mixture was stirred for 1 h at RT. Additional portion of 1Mbromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. Thereaction mixture was stirred at RT overnight, then quenched withmethanol/water. Solid NH₄Cl and DCM were added to the resulting mixtureand the precipitate was filtered off. The organic phase of the filtratewas separated and the aqueous phase was extracted with DCM (3×). Thecombined organic phases were dried over anhydr. Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (DCM/MeOH, 100/0 to 65/35) to yieldCIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)⁺.

Synthesis of INT-1059:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added(NH₄)₂CO₃ (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture wasstirred at RT for 15 min KCN (74.92 g, 1.15 mol, 1.0 eq.) was added. Thereaction mixture was stirred at 60° C. for 18 h and then filtered in hotcondition to get white solid which was washed with water (2.5 L),ethanol (1 L) and hexane (2.5 L). The resulting solid was dried underreduced pressure to getCIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223g, 0.776 mol, 65%) as a white solid. The filtrate was collected frommultiple batches (˜450 g) which contained a mixture of cis and transisomers. The filtrate was concentrated under reduced pressure and solidobtained was filtered and washed with water (1 L) and hexane (1 L).Solid material was dried under reduced pressure to get ˜100 g of amixture of cis and trans (major) isomers. Crude material was partiallydissolved in hot MeOH (600 mL) and cooled to RT, filtered throughsintered funnel, washed with MeOH (200 mL) followed by ether (150 mL)and dried to getTRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50g, 0.174 mmol, ˜9-10%).

Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059)

In analogy to the method described for INT-976 step 2TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione wastreated with LiAlH₄ to be converted intoTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059). Mass: m/z 274.2 (M+H)⁺.

Synthesis of INT-1068 and INT-1069: CIS- andTRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g,230.096 mmol) in MeOH (400 mL) was added NH₄Cl (24.6 g, 460.8 mmol)followed by NH₄OH (400 mL) at RT and the reaction mixture was stirredfor 15 min NaCN (22.5 g, 460.83 mmol) was added and the resultingmixture was stirred for 16 h at RT. The reaction mixture was extractedwith DCM (3×750 mL). Combined organic layer was washed with water (750mL), brine (750 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was triturated with DCM/hexane to get crude1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) asan off white solid which was used in next step without furtherpurification. LC-MS: m/z [M+H]⁺=244.2 (MW calc. 244.09).

Step 2:N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide

To a solution of1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol,3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P(18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirredat RT for 16 h, then diluted with water (100 ml) and extracted with 10%MeOH in DCM (2×250 mL). Combined organic layer was washed with brine(100 mL), dried over Na₂SO₄ and concentrated under reduced pressure toget crudeN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamideas a light yellow sticky material which was used in the next stepwithout further purification. LC-MS: m/z [M+1]⁺=339.9 (MW calc. 339.36).

Step 3:1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

To suspension of LiAlH₄ (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40mL) was addedN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide(6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. Thereaction mixture was stirred at RT for 16 h, then quenched with sat. aq.Na₂SO₄ at 0° C., excess THF was added and the resulting mixture wasstirred at RT for 2 h. The resulting suspension was filtered throughcelite and the filter cake was washed with 10% MeOH in DCM (150 mL).Combined filtrate was concentrated under reduced pressure to yield crude1-aminomethyl-N,N-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, crude) as a light yellow sticky material which was directly usedin the next step without further purification. LC-MS: m/z [M+1]⁺=330.0(MW calc. 329.40).

Step 4: CIS- andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068 and INT-1069)

To a solution of1-aminomethyl-N,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g,76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition ofCOCl₂ (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. andstirred at RT for 16 h. Reaction mixture was basified with sat NaHCO₃solution and extracted with DCM (2×200 ml). Combined organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to get crudeproduct which was purified by prep HPLC to getCIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068) (1.5 g) (major isomer, polar spot on TLC) andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% byHPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]⁺=356.2 (MWcalc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5μ,Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1ml/min, R_(t)=5.17 min ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm)=7.43-7.27 (m,5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz),1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

To a solution ofCIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid oxetan-3-ylmethyl ester (300 mg, 0.636 mmol, 1.0 eq.) in THF/H₂O (8mL, 1.5:1) was added LiOH (160 mg, 3.821 mmol, 6.0 eq.). The reactionmixture was stirred at RT for 16 h, concentrated under reduced pressure,neutralized with aq. NaHSO₄ to pH˜6 and extracted with 5% MeOH/DCM(3×200 mL). the combined organic extract was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was triturated with 15%DCM-Hexane to yieldCIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid (INT-1035) (210 mg, 0.523 mmol, 82%) as an off-white solid.

For further intermediates the synthesis in analogy to previouslydescribed methods is given in the following table. The syntheses of thebuilding blocks and intermediates have either been described previouslywithin this application or can be performed in analogy to the hereindescribed methods or by methods known to the person, skilled in the art.Such a person will also know which building blocks and intermediatesneed to be chosen for synthesis of each exemplary compound.

in analogy m/z Intermediate Chemical Name Chemical structure to method[M + H]⁺ INT-241 CIS-8- (dimethylamino)-1- isobutyl-8-phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-982 330.3 INT-794 CIS-3-(3,4- dimethoxybenzyl)-8- (dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-975 424.3 INT-796 CIS-8-Dimethylamino- 3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy- propyl)-1,3- diazaspiro[4.5]decan-2- one

INT-974 390.3 INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-949 CIS-8-Dimethylamino- 1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-984 302.2 INT-950 CIS-1-(Cyclobutyl-1- methyl)-8- dimethylamino-8-phenyl-3-[phenyl- methyl-1,3- diazaspiro[4.5]decan-2- one

INT-952 432.3 INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)-cyclohexan-1-one

INT-965 238.1 INT-955 4-Dimethylamino-4- thiophen-2-yl- cyclohexan-1-one

INT-965 224.1 INT-956 1-(1-Methyl-1H- pyrazol-3-yl)-4-oxo-cyclohexane-1- carbonitrile

INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1- carbonitrile

INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3-yl)-cyclohexan-1-one

INT-961 222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl- cyclohexan-1-one

INT-961 220.1 INT-962 4-Dimethylamino-4-(3- methoxyphenyl)-cyclohexan-1-one

INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-975 364.2 INT-964 4-(Ethyl-methyl- amino)-4-phenyl- cyclohexan-1-one

INT-965 232.2 INT-967 CIS-8-Dimethylamino- 8-[4-(methoxymethyl-oxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan-2-one

INT-974 454.3 INT-968 CIS-8-Dimethylamino- 8-[3-(methoxymethyl-oxy)-phenyl]-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan-2-one

INT-974 454.3 INT-969 CIS-1-(Cyclobutyl- methyl)-8- dimethylamino-8-(4-hydroxyphenyl)-3-[(4- methoxyphenyl)- methyl]-1,3-diazaspiro[4.5]decan-2-one

INT-971 478.3 INT-970 CIS-8-Dimethylamino- 8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one

SC_2017 424.3 INT-972 CIS-8-Dimethylamino- 8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one

SC_2017 424.3 INT-973 CIS-8-Dimethylamino- 8-(4-fluorophenyl)-3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one

INT-974 412.2 INT-979 CIS-8-Dimethylamino- 1-(3-methoxy-propyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 346.2 INT-980 CIS-8-Dimethylamino- 1-(2-methoxy-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 332.2 INT-981 CIS-8-Dimethylamino- 8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2- one

INT-984 316.2 INT-983 CIS-1-(Cyclopropyl- methyl)-8- dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 328.2 INT-985 CIS-1-(Cyclobutyl- methyl)-8-(methyl-propyl-amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-986 370.3 INT-989 CIS-2-[1-[(1-Cyano- cyclobutyl)-methyl]-8-dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-aceticacid

INT-992 425.2 INT-990 CIS-2-[8- Dimethylamino-1-(3- methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid

INT-992 404.2 INT-991 CIS-2-[1-(Cyclopropyl-1- methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-aceticacid

INT-992 386.2 INT-993 CIS-2-[1-(Cyclobutyl- methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-aceticacid

INT-992 400.3 INT-995 CIS-2-(8- Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3- yl)-acetic acid

INT-992 374.2 INT-996 CIS-2-[8- Dimethylamino-1- [(dimethyl-carbamoyl)-methyl]-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid;2,2,2- trifluoro-acetic acid salt

INT-998 417.2 INT-997 CIS-2-[8- Dimethylamino-1-(2-methoxy-ethyl)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- y]-aceticacid; 2,2,2- trifluoro-acetic acid

INT-998 390.2 INT-999 CIS-2-[1-(Cyclobutyl- methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-aceticacid; 2,2,2- trifluoro-acetic acid salt

INT-998 400.3 INT-1000 4-benzyl-4- (dimethylamino)cyclo- hexanone

INT-965 232.3 INT-1001 CIS-8-benzyl-8- (dimethylamino)-1,3-diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-1002 TRANS-8-benzyl-8- (dimethylamino)-1,3-diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-1009 CIS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2- one

INT-976 280.1 INT-1010 TRANS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2- one

INT-976 280.1 INT-1011 4-(dimethylamino)-4- (1-methyl-1H-benzo[d]imidazol-2- yl)cyclohexanone

INT-965 272.2 INT-1012 CIS-8- (dimethylamino)-8-(1- methyl-1H-benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5] decan-2-one

INT-976 328.2 INT-1013 TRANS-8- (dimethylamino)-8-(1- methyl-1H-benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5] decan-2-one

INT-976 328.2 INT-1014 CIS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetic salt

steps 1 and 2 of INT- 994 332.2 INT-1015 CIS-2-(8-(ethylamino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acidtrifluoroacetate salt

steps 1 and 2 of INT- 994 332.2 INT-1016 TRANS-8- (ethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-1008 274.2 INT-1017 TRANS-2-(8- (ethylamino)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt

steps 1 and 2 of INT- 994 332.2 INT-1018 CIS-8- (dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decane- 2,4-dione

INT-976 288.2 INT-1024 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2- one

INT-977 (step 2) 292.2 INT-1025 CIS-8- (dimethylamino)-8-(4-fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-974, INT-977 (step 2) 292.2 INT-1039 CIS-8- (dimethylamino)-8-(3-(trifluoromethoxy) phenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 358.2 INT-1040 (CIS)-8- (dimethylamino)-8-(3-(trifluoromethyl)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one

INT-1038 342.2 INT-1041 (CIS)-8- (dimethylamino)-8-(3-methoxyphenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 304.2 INT-1042 (CIS)-8-(5- chlorothiophen-2-yl)-8-(dimethylamino)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 314.1 INT-1043 (CIS)-8- (dimethylamino)-8-(3- fluoro-5-methylphenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 306.2 INT-1044 (CIS)-8-(3- chlorophenyl)-8-(dimethylamino)-1,3- diazaspiro[4.5]decan-2- one

INT-1038 308.2 INT-1047 (CIS)-8- (methyl(oxetan-3- ylmethyl)amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-1026 330.5 INT-1057 CIS-1- (cyclobutylmethyl)-8-(dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1031 360.3 INT-1058 CIS-2-(1- (cyclobutylmethyl)-8-(dimethylamino)-8-(4- fluorophenyl)-2-oxo- 1,3- diazaspiro[4.5]decan-3-yl)acetic acid trifluoroacetate

INT-998 418.3 INT-1060 TRANS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt

steps 1 and 2 of INT- 994 332.2 INT-1061 TRANS-1- (cyclopropyl-methyl)-8-dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-984 328.2 INT-1062 TRANS-2-[1- (cyclopropyl-methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-aceticacid trifluoroacetic salt

INT-998 386.2 INT-1063 CIS-1- (cyclopropylmethyl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8-(dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one

INT-987 342.3 INT-1067 TRANS-2-[1- (cyclobutyl-methyl)-8-dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-aceticacid; 2,2,2- trifluoro-acetic acid salt

INT-998 400.3 INT-1070 CIS-8- (dimethylamino)-8- phenyl-1-(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2- one

INT-1068 360.2 INT-1074 CIS-8- (dimethylamino)-8-(3-fluorophenyl)-1-((1- hydroxycyclobutyl) methyl)-1,3-diazaspiro[4.5]decan-2- one

INT-1031 376.2

Synthesis of exemplary compounds Synthesis of SC_1051:CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide

Into a dry reaction vessel were added successively 1 mL of a solution ofCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid (INT-993) (0.1 M in DCM), 2 mL of a solution of5-methoxy-pyridin-2-amine (0.2 M in DCM), 0.07 ml of triethylamine and0.118 mL of a solution of T3P (1.7 M, 50% in EtOAc). The reactionmixture was stirred at RT overnight, then quenched with 3 mL aq. Na₂CO₃(1 M) and stirred at RT for 1 h. The organic layer was separated and theaq. layer was extracted with DCM (2×). The combined organic layers wereconcentrated under reduced pressure and the resulting crude product waspurified by HPLC to obtainCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide(SC_1051). [M+H]⁺ 506.3

Synthesis of SC_1073:CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylicacid amide

To a mixture ofCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid trifluoroacetate (INT-999) (100 mg, 0.19 mmol) and2-amino-N-methylisonicotinamide (118 mg, 0.78 mmol) in DCM (6 ml) wereadded HATU (148 mg, 0.39 mmol) and DIPEA (0.13 ml, 0.78 mmol) at RT andthe reaction mixture was stirred at same temperature for 16 h. Thereaction mixture was washed with 1M aq. Na₂CO₃ (1 mL) and 2M aq. NaOH (1mL). The combined aqueous layers were extracted with DCM (3×5 mL). Thecombined organic layers were washed with water (3 mL) and brine (3 ml),dried over magnesium sulfate, filtered and concentrated in vacuum.Column chromatography (silica gel, cHex/tBuOMe/1N methanolic ammonia1:1:0.05) of the crude product providedCIS-2-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylicacid amide (SC_1073) (27 mg). [M+H]⁺ 533.3

Synthesis of SC_1076:CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylicacid amide

CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide(SC_1026) (30 mg, 0.06 mmol) was dissolved in DMSO (0.2 mL) andpotassium carbonate (17 mg, 0.12 mmol) and hydrogen peroxide (30% inwater, 0.12 mmol) were added at 0° C. The resulting mixture was stirredfor 18 h, then water was added and the reaction mixture was extractedwith DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄,concentrated in vacuo and the resulting crude product was purified byflash chromatography to yieldCIS-6-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylicacid amide SC_1076 (14 mg) as a white solid. [M+H]⁺ 519.3

Synthesis of SC_1110:CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide

A solution ofCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide(SC_1070) (80 mg, 0.16 mmol) in DCM (12 mL) was cooled to 0° C. andtreated with a boron tribromide solution (1M in DCM, 1.26 mL, 1.26mmol). After stirring at RT for 16 h the reaction mixture was quenchedwith MeOH, diluted with water and extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuum. The resulting crude product was purified by columnchromatography (reversed phase silica gel C18, water/MeCN 100:0->20:80)to yieldCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide(SC_1110) (17 mg). [M+H]⁺ 493.3

Synthesis of SC_1128:CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide

CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide(SC_1195) (50 mg, 0.1255 mmol), 4-bromopyrimidine-2-carbonitrile (0.1882mmol), 4,5-XantPhos (0,0188 mmol), Cs₂CO₃ (0.2509 mmol) and Pd₂(dba)₃(0.0063 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixturewas degassed by three consecutive vacuum/nitrogen-refill cycles and thenstirred at 90° C. for 18 h. Water (2 mL) was added and the resultingmixture was extracted with ethyl acetate (3×6 mL). The combined organiclayers were dried over Na₂SO₄, concentrated in vacuo and purified byflash chromatography to yieldCIS-N-(2-cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide(SC_1128) (43 mg) as a white solid. [M+H]⁺ 502.3

Synthesis of SC_1129:CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide

CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamideSC_1120 (30.0 mg) was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol(0.303 mL) and hydrogen peroxide (30% in water, 12 μL) was added. Theresulting mixture was stirred at 60° C. for 1 h. Then sat. aq. Na₂S₂O₃(2 mL) was added and the aqueous layer was extracted with DCM (3×5 mL).The combined organic layers were dried over Na₂SO₄, concentrated invacuo and purified by flash chromatography to yieldCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide(SC_1129) (8 mg) as a white solid. [M+H]⁺ 538.3

Synthesis of SC_1136:CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide

50% Propylphosphonic anhydride (T3P) solution in EtOAc (0.766 mL, 1.204mmol) was added to a solution of crudeCIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid (INT-994) (250 mg, 0.602 mmol), 2-(methylsulfonyl)ethanaminehydrochloride (115.4 mg, 0.723 mmol) and diisopropylethylamine (0.410mL, 2.408 mmol) in DCM (15 mL) at 0° C. The reaction mixture was warmedto RT and stirred for 4 h. The reaction mixture was quenched with waterand the organic product was extracted with DCM (3×20 mL). The combinedorganic layer was washed with sat. aq. NaHCO₃(10 mL), brine (10 mL) anddried over anhydr. Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to give 56 mg (25%) ofCIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide(SC_1136) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.62).[M+H]⁺ 521.3

Synthesis of SC_1138:CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide

CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide(SC_1120) (22 mg) was dissolved in a water/methanol (500 μL/500 μL) andoxone (39 mg) was added. The resulting mixture was stirred at RT for 18h. Then 2N aq. NaOH (2 mL) was added and the aqueous layer was extractedwith DCM (3×5 mL). The combined organic layers were dried over Na₂SO₄,concentrated in vacuo and the residue was purified by flashchromatography to yieldCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide(SC_1138) (14 mg) as a white solid. [M+H]⁺ 554.3

Synthesis of SC_1149:CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide

CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987) (0.2 g, 0.57 mmol) was added to a solution of NaH (60% inmineral oil) (0.15 g, 3.47 mmol) in DMF (5 mL) at RT and the reactionmixture was stirred at RT for 1 h. The reaction mixture was cooled to 0°C. and 2-bromo-N-methylacetamide (0.52 g, 3.47 mmol) in DMF (2 mL) wasadded dropwise. the resulting mixture was stirred for 30 min at 0° C.and then at RT for 16 h. The reaction completion was monitored by TLC.The reaction mixture was quenched with sat. aq. NH₄Cl and the organicproduct was extracted with EtOAc (2×10 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purified of the crude product by preparative TLC using 5% MeOHin DCM as a mobile phase gave 45 g (18%) ofCIS-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide(SC_1149) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3).[M+H]⁺ 417.3

Synthesis of SC_1303:CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide

N-Iodosuccinimide (71.8 mg, 0.319 mmol) was added to a solution ofCIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide(SC_1301) (100 mg, 0.213 mmol) in a mixture of acetonitrile and THF (1:1v/v, 5 mL) at 0° C. and the resulting mixture was stirred at RT for 16h. The reaction mixture was basified with 2N NaOH solution to pH-10 andthe organic product was extracted with ethyl acetate (10 mL×3). Thecombined organic extracts were dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure. The resulting crude product waspurified by preparative reverse phase HPLC to give 50 mg of the desiredproduct as a formiate. The isolated product was diluted with water (5mL) and basified with sat. aq. NaHCO₃. The product was extracted withEtOAc (10 mL×2), combined organic layer was dried over anhydr. Na₂SO₄and concentrated in vacuo to yield 42 mg (43%) ofCIS-2-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide(SC_1303) as an off-white solid (TLC system: 5% MeOH in DCM; Rf: 0.42.).[M+H]⁺ 457.3

Synthesis of SC_1308:CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one

50 wt % solution of T3P (2.32 g, 3.65 mmol) in EtOAc was added to asuspension ofCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-aceticacid hydrochlorid (INT-995) (600 mg, 1.46 mmol),thiomorpholin-1,1-dioxide (237 mg, 1.76 mmol) and diisopropylethylamine(1.27 mL, 7.30 mmol) in THF (10 mL) at 0° C. The reaction mixture waswarmed to RT and stirred for 16 h. The reaction mixture was quenchedwith water, the organic product was extracted with EtOAc (3×25 mL). Thecombined organic extracts were washed with water, brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give thecrude compound. Purification by flash silica column chromatography using4-5% methanol in DCM as eluent yielded 250 mg (34%) ofCIS-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one(SC_1308) as a solid (TLC system: 10% MeOH in DCM Rf: 0.30). [M+H]⁺491.3

Synthesis of SC_1324:CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide

The suspension of TFA salt ofCIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid (500 mg, 1.12 mmol, 1.0 eq.) in THF (40 ml) was cooled to 0° C. andDIPEA (0.78 ml, 4.48 mmol, 4.0 eq.), 1-hydroxy-1H-benzotriazole ammoniumsalt (287 mg, 1.68 mmol, 1.5 eq.) and EDCl (321 mg, 1.68 mmol, 1.5 eq.)were sequentially added. The resulting mixture was stirred at RT for 16h and then concentrated under reduced pressure. Crude product waspurified by column chromatography (neutral alumina; 0.5% NH₃ in 20%MeOH/DCM) to yieldCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (SC_1324) (250 mg, 0.75 mmol, 67%) as an off-whitesolid. [M+H]⁺ 331.2

Synthesis of SC_1332:CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide

KOtBu (1M in THF) (1.4 mL, 1.37 mmol) was added to the solution ofCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (250 mg,0.915 mmol) in THF (15 mL) under argon atmosphere at 0° C. and thereaction mixture was stirred for 30 min 2-Bromo-N-phenylacetamide (312mg, 1.46 mmol) was added, the ice bath was removed and the reactionmixture was stirred for 4 h. Sat. aq. NH₄Cl (10 mL) was added and theresulting mixture was extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried over anhydr. Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by reverse phasepreparative HPLC to give 60 mg (16%) ofCIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide(SC_1332) as a white solid. ¹H NMR (CDCl₃): δ 8.32 (br s, 1H), 7.50-7.48(d, 2H), 7.39-7.36 (m, 2H), 7.33-7.26 (m, 5H), 7.12-7.08 (t, 1H), 5.90(br s, 1H), 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H),1.94-1.91 (m, 2H), 1.58-1.53 (m, 2H). [M+H]⁺ 407.2

Synthesis of SC-1346:CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid tert-butyl ester

KOtBu (187 mg, 1.67 mmol) was added to a solution ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1031) (400 mg, 1.1 mmol) in dry THF (9 mL) at 0° C. The mixture wasstirred for 15 min at this temperature and t-butyl-bromoacetate (0.246mL, 1.67 mmol) was added subsequently. After stirring for 1 h at 0° C.,the reaction was quenched with water, diluted with EtOAc and stirred for5 min at RT. The layers were separated and the aqueous layer wasextracted two times with ethyl acetate. The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by flash chromatography(silica, 0,5 M NH₃ in MeOH/DCM gradient) to yield 395 mg (75%) ofCIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid tert-butyl ester (SC_1346) as a white solid. ¹H NMR (600 MHz, DMSO)δ 7.43-7.36 (m, 1H), 7.17 (d, 1H), 7.13 (dt, 1H), 7.09 (td, 1H), 3.75(d, 2H), 3.21 (s, 2H), 3.05 (d, 2H), 2.67-2.61 (m, 2H), 2.08-2.00 (m,2H), 1.99 (d, 7H), 1.98-1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.75-1.65 (m,2H), 1.39 (d, 8H), 1.38-1.29 (m, 5H). [M+H]⁺ 474.3

of SC-1357:TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-morpholino-2-oxoethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution ofTRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)aceticacid trifluoroacetate (300 mg, 0.6 mmol, 1.0 eq.) in DCM (10 mL) wereadded DIPEA (0.62 mL, 3.6 mmol, 6.0 eq.) and HATU (296 mg, 0.78 mmol,1.3 eq.) followed by morpholine (102 mg, 1.08 mmol, 1.8 eq.) at 0° C.The reaction mixture was stirred at RT for 16 h, then quenched withwater (25 mL) and extracted with DCM (50 mL×2). Combined organic layerwas washed with brine (25 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting crude product waspurified by prep HPLC to getTRANS-1-cyclopropylmethyl-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC-1357) (55 mg, 0.12 mmol, 20%) as a white solid. ¹HNMR (DMSO-d₆, 400MHz), δ (ppm)=7.44-7.29 (m, 5H), 3.96 (s, 2H), 3.56 (bs, 4H), 3.42-3.40(m, 4H), 3.29 (s, 2H), 2.67 (bs, 2H), 2.55-2.54 (d, 2H, J=6.36 Hz), 1.92(s, 6H), 1.56-.144 (m, 6H), 0.51-0.48 (m, 1H), 0.16-0.14 (m, 2H),(−0.26)-(−0.27) (m, 2H). [M+H]⁺ 455.1

Synthesis of INT-1363:TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide

Step 1: tert-butylTRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate

In analogy to the method described for INT-1019 step 1TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1061) was converted into tert-butylTRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate.LC-MS: m/z [M+H]⁺=442.3

Step 2:TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide(INT-1363)

A mixture ofTRANS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-aceticacid tert-butyl ester (250 mg, 0.56 mmol, 1.0 eq.) and 7M NH₃ in MeOH (5mL) was heated in sealed tube at 90° C. for 16 h, then cooled down to RTand concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel basified with aq. NH₃; 10% MeOH inDCM) to yield2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide(77 mg, 0.2 mmol, 35%) as a white solid. LC-MS: m/z [M+1]⁺=385.2 (MWcalc. 384.52); ¹H NMR at 100° C. (DMSO-d₆, 400 MHz), δ (ppm)=7.40-7.29(m, 5H), 6.76 (bs, 2H), 3.68 (s, 2H), 3.33 (s, 2H), 2.61-2.60 (m, 4H),2.00 (s, 6H), 1.61-.153 (m, 6H), 0.58-0.56 (m, 1H), 0.22-0.20 (m, 2H),(−0.16)-(−0.18) (m, 2H).

For further exemplary compounds the last synthesis step in analogy topreviously described methods is given in the following table. Thesyntheses of the building blocks and intermediates have either beendescribed previously within this application or can be performed inanalogy to the herein described methods or by methods known to theperson, skilled in the art. Such a person will also know which buildingblocks and intermediates need to be chosen for synthesis of eachexemplary compound.

in analogy m/z Example Chemical Name Reactant I Reactant II to method[M + H]⁺ SC_1001 CIS-2-[1-(Cyclobutyl-methyl)- INT 9932,5,8,11,14,17,20- SC_1308 721.5 8-dimethylamino-2-oxo-8-heptaoxadocosan- phenyl-1,3- 22-amine diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1002CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3methyl)-8-dimethylamino-2- 6-aminopicolinate oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-2- carboxylic acidmethyl ester SC_1003 CIS-2-[1-(Cyclobutyl-methyl)- INT 993(R)-2-aminopropan-1-ol SC_1308 457.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1R)-2-hydroxy-1-methyl-ethyl]-acetamide SC_1004 CIS-2-[1-(Cyclobutyl-methyl)- INT 993(S)-2-aminopropan-1-ol SC_1308 457.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(1S)-2-hydroxy-1-methyl-ethyl]-acetamide SC_1005 CIS-2-[1-(Cyclobutyl-methyl)- INT 993N-methyl-2- SC_1308 484.3 8-dimethylamino-2-oxo-8-(methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1006CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl 6-aminonicotinate SC_1308 534.3methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester SC_1007CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-methyl-2- SC_1308 498.3methyl)-8-dimethylamino-2- (methylamino)propanamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-2- methyl-propionamideSC_1008 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,2- SC_1308 498.3methyl)-8-dimethylamino-2- dimethylpropanamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,2-dimethyl- propionamideSC_1009 CIS-2-[[2-[1-(Cyclobutyl- INT 993 N,2-dimethyl-2- SC_1308 512.4methyl)-8-dimethylamino-2- (methylamino)propanamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]-methyl-amino]-N,2-dimethyl-propionamide SC_1010 CIS-2-[1-(Cyclobutyl-methyl)- INT 993N,N-dimethyl-2- SC_1308 498.3 8-dimethylamino-2-oxo-8-(methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]- N-methyl-acetamide SC_1011CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-2- SC_1308 484.3methyl)-8-dimethylamino-2- methylpropanamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-2-methyl- propionamide SC_1012CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyridin- SC_1308 506.38-dimethylamino-2-oxo-8- 2-amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyridin-2-yl)- acetamideSC_1013 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin- SC_1308506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamideSC_1014 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin- SC_1308506.3 8-dimethylamino-2-oxo-8- 2-amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamideSC_1015 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3methyl)-8-dimethylamino-2- methylpicolinamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl-pyridine-2-carboxylic acid amide SC_1016 CIS-2-[1-(Cyclobutyl-methyl)-INT 993 cis-3- SC_1308 483.3 8-dimethylamino-2-oxo-8-(aminomethyl)cyclobutanol phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)- methyl]-acetamide SC_1017CIS-2-[1-(Cyclobutyl-methyl)- INT 993 trans-3- SC_1308 483.38-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)- methyl]-acetamideSC_1018 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1308 469.38-dimethylamino-2-oxo-8- (aminomethyl)cyclopropanol phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclopropyl)-methyl]-acetamide SC_1019 CIS-2-[1-(Cyclobutyl-methyl)- INT 9933-amino-1- SC_1308 540.3 8-dimethylamino-2-oxo-8- morpholinopropan-1-onephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-morpholin-4-yl-3-oxo-propyl)-acetamide SC_1020 CIS-N-(1-Cyano-cyclopropyl)- INT 993 1-SC_1308 464.3 2-[1-(cyclobutyl-methyl)-8- aminocyclopropanecarbonitriledimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1021 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3- SC_1308 497.38-dimethylamino-2-oxo-8- (aminomethyl)cyclopentanol phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclopentyl)-methyl]-acetamide SC_1022 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1R)-2-SC_1308 511.4 8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanoldiazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethyl]- acetamide SC_1030CIS-N-(4-Cyano-pyridin-2-yl)- INT 993 2-aminoisonicotinonitrile SC_1308501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1031CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-2- SC_1308507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrimidin-2-yl)- acetamideSC_1032 CIS-2-[[2-[1-(Cyclobutyl- INT 993 methyl 2-aminoisonicotinateSC_1308 534.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-isonicotinic acid methyl esterSC_1033 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyridin-4-amineSC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyridin-4-yl)- acetamideSC_1034 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-fluoropyridin-3-amineSC_1051 494.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-fluoro-pyridin-3-yl)- acetamide SC_1035CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyrimidin-5-amine SC_1051491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)- acetamide SC_1036CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyrimidin-2-amine SC_1051491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)- acetamide SC_1037CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin-2-amine SC_1051494.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)- acetamide SC_1038 CIS-2-[1-(Cyclobutyl-methyl)-INT 993 3-fluoropyridin-4-amine SC_1051 494.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-fluoro-pyridin-4-yl)-acetamide SC_1039 CIS-2-[1-(Cyclobutyl-methyl)- INT 9936-methoxypyridin-3-amine SC_1051 506.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-3-yl)-acetamide SC_1040 CIS-2-[1-(Cyclobutyl-methyl)- INT 9932-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyridin-3-yl)-acetamide SC_1041 CIS-2-[1-(Cyclobutyl-methyl)- INT 9934-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methyl-pyridin-3-yl)-acetamide SC_1042 CIS-2-[1-(Cyclobutyl-methyl)- INT 9933-methylpyridin-4-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methyl-pyridin-4-yl)-acetamide SC_1043 CIS-2-[1-(Cyclobutyl-methyl)- INT 9936-methylpyridin-3-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methyl-pyridin-3-yl)-acetamide SC_1044 CIS-2-[1-(Cyclobutyl-methyl)- INT 9935-fluoropyridin-2-amine SC_1051 494.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-fluoro-pyridin-2-yl)-acetamide SC_1045 CIS-2-[1-(Cyclobutyl-methyl)- INT 9935-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-pyridin-2-yl)-acetamide SC_1046 CIS-2-[1-(Cyclobutyl-methyl)- INT 9934-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (4-methyl-pyridin-2-yl)-acetamide SC_1047 CIS-2-[1-(Cyclobutyl-methyl)- INT 9933-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methyl-pyridin-2-yl)-acetamide SC_1048 CIS-2-[1-(Cyclobutyl-methyl)- INT 9933-methoxypyridin-4-amine SC_1051 506.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (3-methoxy-pyridin-4-yl)-acetamide SC_1049 CIS-2-[1-(Cyclobutyl-methyl)- INT 9936-methoxypyridazin-3- SC_1051 507.3 8-dimethylamino-2-oxo-8- aminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridazin-3-yl)-acetamide SC_1050 CIS-2-[1-(Cyclobutyl-methyl)- INT 9935-(methylsulfonyl)pyridin- SC_1051 554.3 8-dimethylamino-2-oxo-8-2-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)- acetamide SC_1052CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylsulfonyl)pyridin- SC_1051554.3 8-dimethylamino-2-oxo-8- 3-amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-methylsulfonyl-pyridin-3-yl)- acetamideSC_1053 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrazin-2-amineSC_1051 507.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrazin-2-yl)- acetamideSC_1054 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin-2-amineSC_1051 506.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamideSC_1055 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-2-SC_1051 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-2-yl)- acetamideSC_1056 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-5-ylmethanamineSC_1051 480.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (oxazol-5-yl-methyl)-acetamide SC_1057CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-2-ylmethanamine SC_1051480.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide SC_1058 CIS-1-(Cyclobutyl-methyl)-3- INT993 (3S,4S)-piperidine-3,4-diol SC_1051 499.3 [2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1059 CIS-1-(Cyclobutyl-methyl)-3- INT 993(3S,4S)-pyrrolidine-3,4-diol SC_1051 485.3 [2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1060 CIS-1-(Cyclobutyl-methyl)-3- INT 993(3S,4R)-pyrrolidine-3,4-diol SC_1051 485.3 [2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1061 CIS-2-[1-(Cyclobutyl-methyl)- INT 993cyclopropanamine SC_1051 439.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- cyclopropyl-acetamide SC_1062CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(methylamino)ethanol SC_1051457.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl- acetamide SC_1063CIS-1-(Cyclobutyl-methyl)-8- INT 993 piperidin-3-ol SC_1051 483.3dimethylamino-3-[2-(3- hydroxy-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1064CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1051 483.38-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclobutyl)- methyl]-acetamideSC_1065 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1051 484.3methyl)-8-dimethylamino-2- dimethylacetamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- acetamideSC_1066 CIS-1-(Cyclobutyl-methyl)-8- INT 993 5,6,7,8-tetrahydro- SC_1051506.3 dimethylamino-3-[2-oxo-2- [1,2,4]triazolo[1,5-(5,6,7,8-tetrahydro- a]pyrazine [1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1067CIS-3-[[2-[1-(Cyclobutyl- INT 993 3-amino-N,N- SC_1051 498.3methyl)-8-dimethylamino-2- dimethylpropanamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N,N-dimethyl- propionamideSC_1068 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20,23-octa-SC_1308 765.5 8-dimethylamino-2-oxo-8- oxapentacosan-25-aminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1069 CIS-2-[1-(Cyclobutyl-methyl)-INT 993 4-methoxypyrimidin-5- SC_1308 507.3 8-dimethylamino-2-oxo-8-amine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)- acetamide SC_1070CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin-5- SC_1308507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyrimidin-5-yl)- acetamideSC_1072 CIS-N-(5-Cyano-pyridin-2-yl)- INT 993 6-aminonicotinonitrileSC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1074CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-4- SC_1308507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (5-methoxy-pyrimidin-4-yl)- acetamideSC_1075 CIS-N-(2-Cyano-pyrimidin-5- INT 993 5-aminopyrimidine-2- SC_1308502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitriledimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1077 CIS-N-(3-Cyano-pyridin-2-yl)- INT 993 2-aminonicotinonitrileSC_1308 501.3 2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1078CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1079 CIS-6-[[2-[1-(Cyclobutyl- SC 1072 —SC_1076 519.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-3- carboxylic acidamide SC_1080 CIS-N-(4-Cyano-pyrimidin-2- INT 993 2-aminopyrimidine-4-SC_1308 502.3 yl)-2-[1-(cyclobutyl-methyl)-8- carbonitriledimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1081 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1,3,4-thiadiazol-2-amineSC_1051 483.2 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- ([1,3,4]thiadiazol-2-yl)- acetamideSC_1082 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 thiazol-2-amine SC_1051482.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide SC_1083 CIS-2-[1-(Cyclobutyl-methyl)- INT 9935-methylisoxazol-3-amine SC_1051 480.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (5-methyl-isoxazol-3-yl)-acetamide SC_1084 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 isoxazol-3-amineSC_1051 466.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- isoxazol-3-yl-acetamide SC_1085CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-methyl-1H-pyrazol-3- SC_1051479.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (1-methyl-1H-pyrazol-3-yl)- acetamideSC_1086 CIS-N-(4-Cyano-5- INT 993 3-amino-5-(methylthio)-1H- SC_1051536.3 methylsulfanyl-1H-pyrazol-3- pyrazole-4-carbonitrileyl)-2-[1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1087CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrazin-2-amine SC_1051507.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)- acetamide SC_1088CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4-ylmethanamine SC_1051491.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)- acetamide SC_1089 CIS-2-[1-(Cyclobutyl-methyl)-INT 993 2-(aminomethyl)phenol SC_1051 505.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-hydroxyphenyl)-methyl]-acetamide SC_1090 CIS-2-[1-(Cyclobutyl-methyl)- INT 993(1-methyl-1H-imidazol-4- SC_1051 493.3 8-dimethylamino-2-oxo-8-yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)- methyl]-acetamide SC_1091CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methylpyridin-3- SC_1051 504.38-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(4-methyl-pyridin-3-yl)-methyl]-acetamide SC_1092 CIS-2-[1-(Cyclobutyl-methyl)- INT 993pyrimidin-2-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-2-yl-methyl)-acetamide SC_1093 CIS-2-[1-(Cyclobutyl-methyl)- INT 993pyridazin-3-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide SC_1094 CIS-2-[1-(Cyclobutyl-methyl)-INT 993 pyrimidin-4-ylmethanamine SC_1051 491.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-4-yl-methyl)-acetamide SC_1095 CIS-2-[1-(Cyclobutyl-methyl)- INT 993pyrazin-2-ylmethanamine SC_1051 491.3 8-dimediylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide SC_1096 CIS-2-[1-(Cyclobutyl-methyl)-INT 993 oxazol-4-ylmedianamine SC_1051 480.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (oxazol-4-yl-methyl)-acetamideSC_1097 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methylpyridin-3-SC_1051 504.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(2-methyl-pyridin-3-yl)-methyl]-acetamide SC_1098 CIS-2-[1-(Cyclobutyl-methyl)- INT 993(2-methoxypyridin-3- SC_1051 520.3 8-dimethylamino-2-oxo-8-yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)- methyl]-acetamide SC_1099CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyridin-3- SC_1051 520.38-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(4-methoxy-pyridin-3-yl)-methyl]-acetamide SC_1100 CIS-2-[1-(Cyclobutyl-methyl)- INT 993(6-methylpyridin-2- SC_1051 504.3 8-dimethylamino-2-oxo-8-yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)- methyl]-acetamide SC_1101CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methoxypyridin-2- SC_1051 520.38-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(6-methoxy-pyridin-2-yl)-methyl]-acetamide SC_1102 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-SC_1051 519.3 8-dimethylamino-2-oxo-8- methoxyphenyl)methanaminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(2-methoxyphenyl)-methyl]-acetamide SC_1103 CIS-2-[1-(Cyclobutyl-methyl)- INT 993o-tolylmethanamine SC_1051 503.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (o-tolyl-methyl)-acetamide SC_1104CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3methyl)-8-dimethylamino-2- methylnicotinamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl-pyridine-3-carboxylic acid amide SC_1105 CIS-2-[[2-[1-(Cyclobutyl- SC1030 — SC_1076 519.3 methyl)-8-dimethylamino-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-pyridine-4- carboxylic acidamide SC_1106 CIS-2-[1-(Cyclobutyl-methyl)- INT 9936-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- aminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrimidin-4-yl)-acetamide SC_1107 CIS-2-[1-(Cyclobutyl-methyl)- INT 9932-methoxypyrimidin-4- SC_1308 507.3 8-dimethylamino-2-oxo-8- aminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-pyrimidin-4-yl)-acetamide SC_1109 CIS-2-[1-(Cyclobutyl-methyl)- SC 1069 SC_1110 493.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)- acetamide SC_1111CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-3-ol SC_1308 492.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)- acetamide SC_1112CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-aminotetrahydro-2H- SC_1308531.3 8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1113CIS-1-(Cyclobutyl-methyl)-8- INT 993 thiomorpholine 1,1-dioxide SC_1308517.3 dimethylamino-3-[2-(1,1-dioxo- [1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1114CIS-2-[8-Dimethylamino-1-(2- INT 997 pyrimidin-4-amine SC_1308 467.3methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1115 CIS-2-[8-Dimethylamino-1-(2- INT 997methylamine SC_1308 403.3 methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1117CIS-N-(5-Cyano-pyrimidin-4- INT 993 4-aminopyrimidine-5- SC_1308 502.3yl)-2-[1-(cyclobutyl-methyl)-8- carbonitriledimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1118 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylthio)pyridin-2-SC_1308 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (5-methylsulfanyl-pyridin-2-yl)- acetamideSC_1119 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-2-SC_1308 507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyrimidin-2-yl)- acetamideSC_1120 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylthio)pyridin-2-SC_1308 522.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-methylsulfanyl-pyridin-2-yl)- acetamideSC_1121 CIS-2-[8-Dimethylamino-1-(2- INT 997 2-aminoethanol SC_1308433.3 methoxy-ethyl)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1122 CIS-2-[[2-[8-Dimethylamino-1- INT997 2-aminoacetamide SC_1308 446.3 (2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1123CIS-2-[1-(Cyclobutyl-methyl)- INT 993 methylamine SC_1308 413.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1124 CIS-2-[1-(Cyclobutyl-methyl)- INT 9932-aminoethanol SC_1308 443.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1125CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-2-ol SC_1308 492.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)- acetamide SC_1126CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyrimidin-5- SC_1308521.3 8-dimethylamino-2-oxo-8- yl)methanamine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide SC_1127 CIS-2-[1-(Cyclobutyl-methyl)- INT 993(4-methoxypyrimidin-2- SC_1308 521.3 8-dimethylamino-2-oxo-8-yl)methanamine phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)- methyl]-acetamide SC_1130CIS-2-[[2-[1-(Cyclobutyl- SC 1011 2-amino-2- SC_1303 470.3methyl)-8-methylamino-2-oxo- methylpropanamide 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-2-methyl- propionamidc SC_1131CIS-2-[[2-[1-(Cyclobutyl- SC 1222 — SC_1303 456.3methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl- acetamide SC_1132 CIS-2-[[2-[1-(Cyclobutyl- SC1078 — SC_1303 442.3 methyl)-8-methylamino-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1133CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-(2- SC_1308 545.48-dimethylamino-2-oxo-8- methoxyethoxy)ethoxy)- phenyl-1,3- ethanaminediazaspiro[4.5]decan-3-yl]-N- [2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide SC_1134 CIS-N-(Carbamoyl-methyl)-2- SC 11462-(methylamino)acetamide SC_1303 456.3 [1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1135 CIS-2-[1-(Cyclobutyl-methyl)- SC 1005N-methyl-2- SC_1303 470.3 8-methylamino-2-oxo-8-phenyl-(methylamino)acetamide 1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1137CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyrimidin-5-amine SC_1136 493.3hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyrimidin-5-yl-acetamide SC_1139CIS-2-[8-Dimethylamino-1- INT 996 2-aminoethanol SC_1308 460.3[(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1140CIS-2-[[2-[1-(Cyclobutyl- SC 1007 — SC_1303 484.3methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2- methyl-propionamide SC_1141CIS-1-(Cyclobutyl-methyl)-3- SC 1214 — SC_1303 503.3[2-(1,1-dioxo-[1,4]thiazinan-4- yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1142CIS-2-[1-(Cyclobutyl-methyl)- SC 1199 — SC_1303 707.58-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamide SC_1143CIS-2-[[2-[1-(Cyclobutyl- SC 1065 — SC_1303 470.3methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl- acetamide SC_1144CIS-2-[1-(Cyclobutyl-methyl)- SC 1070 — SC_1110 493.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)- acetamide SC_1145CIS-2-[1-(Cyclobutyl-methyl)- SC 1321 — SC_1138 554.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)- acetamide SC_1146CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3methyl)-8-dimethylamino-2- methylacetamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1147CIS-N-(Carbamoyl-methyl)-2- INT 993 2-(methylamino)acetamide SC_1308470.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1148CIS-2-(8-Dimethylamino-2- INT 995 methylamine SC_1136 387.3oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide SC_1150 CIS-2-[1-(Cyclobutyl-methyl)- SC 1321 — SC_1129538.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2- yl]-acetamide SC_1151CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminopyridin-3-ol SC_1308 492.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)- acetamide SC_1152CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2- SC_1308 505.38-dimethylamino-2-oxo-8- (methylsulfonyl)ethanamine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-methylsulfonyl-ethyl)- acetamideSC_1154 CIS-1-(Cyclobutyl-methyl)-3- INT 993(3S,4R)-pyrrolidine-3,4-diol SC_1308 485.3 [2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1155 CIS-2-[1-(Cyclobutyl-methyl)- SC 1198— SC_1303 429.3 8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- N-(2-hydroxy-ethyl)-acetamide SC_1156CIS-2-[8-Dimethylamino-1- INT 996 pyrimidin-4-amine SC_1308 494.3[(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1157CIS-2-[8-Dimethylamino-1- INT 996 methylamine SC_1308 430.3[(dimethyl-carbamoyl)-methyl]- 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1158CIS-2-[[2-[8-Dimethylamino-1- INT 992 2-aminoacetamide SC_1136 444.3(2-methyl-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1159 CIS-2-[8-Dimethylamino-1-[(1- INT 994NH₄Cl SC_1136 415.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1160CIS-2-[8-Dimethylamino-1-[(1- INT 994 methylamine SC_1136 429.3hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1161CIS-2-[[2-[8-Dimethylamino-1- INT 987 N-(2-amino-2-oxoethyl)-2- SC_1149460.3 (3-methoxy-propyl)-2-oxo-8- bromoacetamide phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1162CIS-2-[8-Dimethylamino-1-(2- INT 984 2-bromo-N- SC_1149 401.3methyl-propyl)-2-oxo-8-phenyl- methylacetamide1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1163CIS-1-(Cyclobutyl-methyl)-3- SC 1154 — SC_1303 471.3[2-[(3S,4R)-3,4-dihydroxy- pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1164CIS-2-[8-Dimethylamino-1-[(1- INT 998 methylamine SC_1308 427.3methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1165CIS-2-[8-Dimethylamino-1-[(1- INT 998 pyrimidin-4-amine SC_1308 491.3methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1166CIS-2-[[2-[8-Dimethylamino-1- INT 998 2-aminoacetamide SC_1308 470.3[(1-methyl-cyclobutyl)-methyl]- 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1167CIS-2-[8-Dimethylamino-1-[(1- INT 998 2-aminoethanol SC_1308 457.3methyl-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1168CIS-2-[[2-[1-(Cyclopropyl- INT 983 N-(2-amino-2-oxoethyl)-2- SC_1149442.3 methyl)-8-dimethylamino-2- bromoacetamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1169CIS-2-[1-(Cyclobutyl-methyl)- INT 986 2-bromo-N- SC_1149 427.38-(ethyl-methyl-amino)-2-oxo- methylacetamide 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1171CIS-2-[[2-(8-Dimethylamino-2- INT 995 2-aminoacetamide SC_1308 430.3oxo-8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide SC_1172 CIS-2-[[2-[8-Dimethylamino-1- INT 9942-aminoacetamide SC_1308 472.3 [(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide SC_1173 CIS-2-[8-Dimethylamino-1-[(1- INT 9942-aminoethanol SC_1308 459.3 hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1174 CIS-2-[8-Dimethylamino-1-[(1- INT994 4-aminotetrahydro-2H- SC_1308 547.3 hydroxy-cyclobutyl)-methyl]-2-thiopyran 1,1-dioxide oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)- acetamide SC_1175 CIS-2-[1-(Cyclopropyl-methyl)-INT 983 2-bromo-N- SC_1149 399.3 8-dimethylamino-2-oxo-8-methylacetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1176 CIS-2-[1-[(1-Cyano- INT 951 2-bromo-N- SC_1149438.3 cyclobutyl)-methyl]-8- methylacetamidedimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1177 CIS-2-[1-(Cyclobutyl-methyl)- INT 9982-aminoethanol SC_1308 457.3 8-(ethyl-methyl-amino)-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1178CIS-2-[[2-[1-(Cyclobutyl- INT 998 2-aminoacetamide SC_1308 470.3methyl)-8-(ethyl-methyl- amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1179CIS-2-[[2-[1-(Cyclobutyl- SC 1008 — SC_1303 484.3methyl)-8-methylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl- propionamide SC_1180CIS-2-[8-Dimethylamino-1-(3- INT 990 2-aminoethanol SC_1308 447.3methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide SC_1181 CIS-2-[8-Dimethylamino-1-(3- INT 990N-methyl-2- SC_1308 488.3 methoxy-propyl)-2-oxo-8-(methylamino)acetamide phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl- methyl)-acetamide SC_1182CIS-8-Dimethylamino-1-(3- INT 990 piperazin-2-one SC_1308 486.3methoxy-propyl)-3-[2-oxo-2-(3- oxo-piperazin-1-yl)-ethyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1183 CIS-N-(Carbamoyl-methyl)-2- INT 9902-(methylamino)acetamide SC_1308 474.3 [8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1184 CIS-2-[8-Dimethylamino-1-(3- INT 990 cis-3-SC_1073 487.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanolphenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- |(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1185 CIS-2-[8-Dimethylamino-1-(3- INT 990 trans-3-SC_1073 487.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanolphenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclobutyl)-methyl]-acetamide SC_1186 CIS-2-[8-Dimethylamino-1-(3- INT 990 3-SC_1073 501.3 methoxy-propyl)-2-oxo-8- (aminomethyl)cyclopentanolphenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(3-hydroxy-cyclopentyl)-methyl]-acetamide SC_1187 CIS-2-[8-Dimethylamino-1-(3- INT 990pyridazin-4-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridazin-4-yl-acetamide SC_1188CIS-2-[8-Dimethylamino-1-(3- INT 990 6-methoxypyridin-2-amine SC_1308510.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)- acetamide SC_1189 CIS-N-(2-Cyanoethyl)-2-[8-INT 990 3-aminopropanenitrile SC_1308 456.3 dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetamideSC_1190 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-5-amine SC_1308481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1191 CIS-2-[8-Dimethylamino-1-(3- INT 990pyrimidin-4-amine SC_1308 481.3 methoxy-propyl)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1192CIS-2-[1-(Cyclobutyl-methyl)- INT 999 6-methoxypyridin-2-amine SC_1073520.3 8-(ethyl-methyl-amino)-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyridin-2-yl)- acetamideSC_1193 CIS-2-[8-Dimediylamino-1-[(1- INT 995 pyridin-3-amine SC_1308492.3 hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridin-3-yl-acetamide SC_1195CIS-2-[1-(Cyclobutyl-methyl)- INT 999 NH₄Cl SC_1073 399.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetamide SC_1196 CIS-2-[1-(Cyclobutyl-methyl)- INT 999pyrimidin-4-amine SC_1073 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyrimidin-4-yl-acetamide SC_1197CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-methoxyethanamine SC_1073 457.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1198 CIS-2-[1-(Cyclobutyl-methyl)- INT999 2-aminoethanol SC_1073 443.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-ethyl)-acetamide SC_1199CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.58-dimethylamino-2-oxo-8- heptaoxadocosan-22-amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethyl]- acetamideSC_1201 CIS-2-[1-(Cyclobutyl-methyl)- SC 1229 — SC_1303 399.38-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1203 CIS-(2S)-1-[2-[1-(Cyclobutyl- INT 993(S)-pyrrolidine-2- SC_1308 496.3 methyl)-8-dimethylamino-2- carboxamideoxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylie acid amide SC_1204CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1308 484.3methyl)-8-dimethylamino-2- dimethylacetamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N.N-dimethyl- acetamideSC_1205 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxetan-3-amine SC_1308455.3 8-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide SC_1206 CIS-2-[[2-[1-(Cyclobutyl- INT 9932-aminoacetamide SC_1308 456.3 methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamideSC_1207 CIS-1-(Cyclobutyl-methyl)-8- INT 999 piperazin-2-one SC-1073482.3 dimethylamino-3-[2-oxo-2-(3- oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1208CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-aminotetrahydro-2H- SC_1073531.3 8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (1,1-dioxo-thian-4-yl)- acetamide SC_1209CIS-1-(Cyclobutyl-methyl)-8- INT 999 morpholin-2-ylmethanol SC_1073499.3 dimethylamino-3-[2-[2- (hydroxymethyl)-morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1210CIS-N-(Carbamoyl-methyl)-2- INT 993 2-(methylamino)acetamide SC_1308470.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- N-methyl-acetamide SC_1211CIS-N-(Cyano-methyl)-2-[1- INT 993 2-aminoacetonitrile SC_1308 438.3(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1212CIS-N-(2-Acetylamino-ethyl)-2- INT 993 N-(2-aminoethyl)acetamide SC_1308484.3 [1-(cyclobutyl-methyl)-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetamide SC_1213CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-(methylsulfonyl)ethan- SC_1073505.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-methylsulfonyl-ethyl)- acetamideSC_1214 CIS-1-(Cyclobutyl-methyl)-8- INT 999 thiomorpholine 1,1-dioxideSC_1073 517.3 dimethylamino-3-[2-(1,1-dioxo- [1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1215CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-(aminomethyl)tetra- SC_1073545.3 8-dimethylamino-2-oxo-8- hydro-2H-thiopyran 1,1- phenyl-1,3-dioxide diazaspiro[4.5]decan-3-yl]-N- [(1,1-dioxo-thian-4-yl)-methyl]-acetamide SC_1216 CIS-1-(Cyclobutyl-methyl)-8- INT 9991-(methylsulfonyl)- SC_1073 546.3 dimethylamino-3-[2-(4- piperazinemethylsulfonyl-piperazin-1-yl)- 2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1217 CIS-N-(2-Cyanoethyl)-2-[1- INT 9933-aminopropanenitrile SC_1308 452.3 (cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1218 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-amino-2-methylpropan-2-SC_1308 471.3 8-dimethylamino-2-oxo-8- ol phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-hydroxy-2-methyl-propyl)- acetamideSC_1219 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-amino-1- SC_1308 526.38-dimethylamino-2-oxo-8- morpholinoethanone phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-morpholin-4-yl-2-oxo-ethyl)- acetamideSC_1220 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-aminoethoxy)ethanolSC_1308 487.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [2-(2-hydroxy-ethoxy)-ethyl]- acetamideSC_1222 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3methyl)-8-dimethylamino-2- methylacetamide oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-N-methyl- acetamide SC_1223CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-(2-aminoethyl)- SC_1308 520.38-dimethylamino-2-oxo-8- methanesulfonamide phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [2-(methanesulfonamido)- ethyl]-acetamideSC_1224 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-(aminomethyl)- SC_1308497.3 8-dimethylamino-2-oxo-8- cyclopentanol phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- [(1-hydroxy-cyclopentyl)-methyl]-acetamide SC_1225 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-SC_1308 511.4 8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanolphenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [(4-hydroxy-cyclohexyl)-methyl]-acetamide SC_1226 CIS-2-[1-(Cyclobutyl-methyl)- INT 9932-(2-methoxyethoxy)- SC_1308 501.3 8-dimethylamino-2-oxo-8- ethanaminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(2-methoxy-ethoxy)-ethyl]-acetamide SC_1227 CIS-2-[1-(Cyclobutyl-methyl)- INT 993N¹,N¹-dimethylethane-1,2- SC_1308 470.3 8-dimethylamino-2-oxo-8- diaminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- [2-(dimethylamino)ethyl]-acetamide SC_1228 CIS-2-[1-(Cyclobutyl-methyl)- INT 953 2-bromo-N-SC_1149 455.3 8-[methyl-(2-methyl-propyl)- methylacetamideamino]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1229 CIS-2-[1-(Cyclobutyl-methyl)- INT 999methylamine SC_1073 413.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- methyl-acetamide SC_1230CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4-amine SC_1051 477.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide SC_1231 CIS-2-[1-(Cyclobutyl-methyl)- INT 9936-methylpyridin-2-amine SC_1051 490.3 8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N- (6-methyl-pyridin-2-yl)-acetamide SC_1232 CIS-2-[1-(Cyclobutyl-methyl)- INT 993pyridazin-3-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridazin-3-yl-acetamide SC_1233CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-5-amine SC_1051 477.38-dimethylamino-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide SC_1234 CIS-2-[1-(Cyclobutyl-methyl)- INT 993pyridazin-4-amine SC_1051 477.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridazin-4-yl-acetamide SC_1235CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin-4- SC_1051507.3 8-dimethylamino-2-oxo-8- amine phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (6-methoxy-pyrimidin-4-yl)- acetamideSC_1236 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin-4-amineSC_1051 490.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-methyl-pyridin-4-yl)- acetamide SC_1300CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyridin-4-amine SC_1308 492.3hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridin-4-yl-acetamide SC_1301CIS-2-[8-Dimethylamino-1-[(1- INT 994 oxetan-3-amine SC_1308 471.3hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (oxetan-3-yl)-acetamide SC_1302CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-methoxyethanamine SC_1308 473.3hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (2-methoxy-ethyl)-acetamide SC_1304CIS-2-[1-[(1-Hydroxy- SC 1301 — SC_1303 459.3 cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide SC_1305 CIS-2-[8-Dimethylamino-1-(3- SC1302 — SC_1308 510.3 methoxy-propyl)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (4-methoxy-pyridin-2-yl)- acetamideSC_1306 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4-ylmethanamineSC_1073 495.3 methoxy-propyl)-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- (pyrimidin-4-yl-methyl)- acetamide SC_1309CIS-2-[8-Dimethylamino-1-[(1- SC 1159 — SC_1128 492.3hydroxy-cyclobutyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridin-2-yl-acetamide SC_1310CIS-2-[1-[(1-Cyano- INT 989 NH₄Cl SC_1308 424.3 cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1311 CIS-2-[[2-[1-[(1-Cyano- INT 989 2-aminoacetamide SC_1308 481.3cyclobutyl)-methyl]-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- acetyl]amino]-acetamide SC_1312CIS-2-[1-[(1-Hydroxy- SC 1160 — SC_1303 415.3 cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide SC_1313 CIS-3-[2-(1,1-Dioxo- SC 1308 — SC_1303 477.2[1,4]thiazinan-4-yl)-2-oxo- ethyl]-8-methylamino-8-phenyl- 1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_1317 CIS-2-[1-(Cyclobutyl-methyl)- INT 993pyridin-2-amine SC_1051 476.3 8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N- pyridin-2-yl-acetamide SC_1318CIS-8-Dimethylamino-1-[(1- INT 994 morpholine SC_1136 485.3hydroxy-cyclobutyl)-methyl]-3- (2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_1319 CIS-2-[1-[(1-Hydroxy-SC 1159 — SC_1303 401.2 cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]- acetamideSC_1320 CIS-1-(Cyclobutyl-methyl)-8- INT 993 morpholine SC_1308 469.3dimethylamino-3-(2-morpholin- 4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_1321 CIS-2-[1-(Cyclobutyl-methyl)- INT 9934-(methylthio)pyridin-2- SC_1073 522.3 8-dimethylamino-2-oxo-8- aminephenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)- acetamide

in analogy ¹H NMR m/z Example Chemical name Reactant I Reactant II tomethod data (M + H)⁺ SC_1322 CIS-3-[2-(1,1- INT-1014 thiomorpholin-SC_1308 ¹HNMR (DMSO-d6, 400 435.3 Dioxo- 1,1-dioxide (for step 1), MHz),δ (ppm) = 7.40 (d, [1,4]thiazinan-4- SC_1303 2H, J = 7.2 Hz),yl)-2-oxo-ethyl]- (for step 2) 7.31 (t, 2H, J = 7.44 Hz),8-methylamino-8- 7.18 (t, 1H, J = 6.78 Hz), phenyl-1,3- 6.61 (bs, 1H),3.98 (s, diazaspiro[4.5]decan- 2H), 3.82 (bs, 4H), 2-one 3.21 (bs, 4H),3.09 (s, 2H), 1.95 (t, 2H, J = 11.74 Hz), 1.85 (bs, 5H), 1.65 (bs, 2H),1.48 (bs, 2H). SC_1323 CIS-2-(8- SC_1324 SC_1303 ¹HNMR (DMSO-d6, 317.2Methylamino-2- 400 MHz), δ (ppm) = oxo-8-phenyl-1,3- 7.41 (d,diazaspiro[4.5]decan- 2H, J = 7.60 Hz), 7.30 (t, 3-yl)-acetamide 2H, J =7.60 Hz), 7.23 (s, 1H), 7.18 (t, 1H, J = 7.08 Hz), 6.95 (s, 1H), 6.58(s, 1H), 3.58 (s, 2H), 3.21 (s, 2H), 1.96 − 1.80 (m, 7H), 1.69 − 1.66(m, 2H), 1.47 (d, 2H, J = 11.76 Hz). SC_1324 CIS-2-(8- INT-1014procedure — 331.2 Dimethylamino-2- described oxo-8-phenyl-1,3-diazaspiro[4.5]decan- 3-yl)-acetamide SC_1325 CIS-3-[2-(1,1- INT-1015thiomorpholin- SC_1308 ¹HNMR (DMSO-d6, 400 449.4 Dioxo- 1,1-dioxide (forstep 1), MHz), δ (ppm) = 7.42 (d, [1,4]thiazinan-4 SC_1303 2H, J = 7.2Hz), 7.29 (t, 2H, yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.17 (t,1H), 8-ethylamino-8- 6.61 (s, 1H), 5.75 (s, 1H), phenyl-1,3- 3.98 (s,2H), 3.82 (s, 4H), diazaspiro[4.5]decan- 3.21 (s, 4H), 3.09 (s, 2H),2-one 2.07 − 1.93 (m, 4H), 1.87 − 1.83 (m, 2H), 1.69 − 1.66 (m, 2H),1.48 − 1.45 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1326 TRANS-3-[2-INT-1017 thiomorpholin- SC_1308 ¹HNMR (DMSO-d6, 400 449.2 (1,1-Dioxo-1,1-dioxide (for step 1), MHz), δ (ppm) = 7.50 (d, [1,4]thiazinan-4-SC_1303 2H, J = 7.4 Hz), 7.30 (t 2H, yl)-2-oxo-ethyl]- (for step 2) J =7.2 Hz), 7.18 − 7.15 (m, 8-ethylamino-8- 2H), 4.00 (s, 2H), 3.84 (bs,phenyl-1,3- 4H), 3.24 (s, 2H), 3.19 (s, diazaspiro[4.5]decan- 2H), 3.11(s, 2H), 2.07 − 2-one 1.44 (m, 11H), 0.91 (t, 3H, J = 6.6 Hz). SC_1327CIS-2-[1- INT-998 methylamine SC_1308 ¹H NMR (DMSO-d6, δ 399.3(Cyclobutyl- (step 1) (for step 1), 7.71 − 7.70 (m, 1H), 7.43 methyl)-8-SC_1303 (d, 2H), 7.30 (t, 2H), 7.18 (t, methylamino-2- (for step 2) 1H),3.64 (s, 2H), 3.21 (s, oxo-8-phenyl-1,3- 2H), 3.08 (d, 2H), 2.57 −diazaspiro[4.5]decan- 2.54 (m, 4H), 2.25 (m, 1H), 3-yl]-N- 2.11-2.06 (m,2H), 1.97 − methyl-acetamide 1.82 (m, 7H), 1.80 − 1.67 (m, 4H), 1.59 (m,2H), 1.36 − 1.35 (m, 2H). SC_1328 CIS-2-(8- INT-1015 SC_1324 ¹HNMR(DMSO-d6, 400 331.1 Ethylamino-2- MHz) δ (ppm) = 7.43 (d,oxo-8-phenyl-1,3- 2H, J = 7.6 Hz), 7.29 (t, 2H, diazaspiro[4.5]decan- J= 7.2 Hz), 7.22 (s, 1H), 3-yl)-acetamide 7.17 (t, 1H, J = 6.8 Hz), 6.95(s, 1H), 6.58 (s, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.07 − 2.05 (m, 2H),1.93 (t, 2H, J = 11.2), 1.85 − 1.82 (m, 2H), 1.69 − 1.67 (m, 2H,), 1.48− 1.45 (m, 2H), 0.92 (t, 3H, J = 6.8 Hz). SC_1329 TRANS-2-(8- INT-1017SC_1324 ¹HNMR (DMSO-d6, 400 331.2 Ethylamino-2- MHz) δ (ppm) = 7.49 (d,oxo-8-phenyl-1,3- 2H, J = 7.56 Hz), 7.29 (t, diazaspiro[4.5]decan- 2H, J= 7.66 Hz), 7.24 (s, 3-yl)-acetamide 1H), 7.16 (t, 1H), 7.24 Hz), 7.11(bs, 1H), 6.98 (bs, 1H), 3.59 (s, 2H), 3.17 (s, 2H), 2.09 − 1.95 (m,4H). SC_1330 CIS-2-(8- INT-1014 2- SC_1308 ¹HNMR (DMSO-d6, 400 389.2Dimethylamino-2- (methylamino)- MHz at 100 0C.), δ (ppm) =oxo-8-phenyl-1,3- ethanol 7.34 − 7.23 (m, 5H), 6.41diazaspiro[4.5]decan- (s, 1H), 4.4 (bs, 1H), 3.89 3-yl)-N-(2- (s, 2H),3.53 − 3.52 (m, 2H), hydroxy-ethyl)-N- 3.34 (t, 2H, J = 5.56 Hz),methyl-acetamide 3.13 (s, 2H), 2.89 (s, 2H), 2.31 − 2.27 (m, 2H), 2.01(s, 6H), 1.89 − 1.78 (m, 4H), 1.46 − 1.41 (m, 2H). SC_1331 CIS-8-INT-1020 1,4-thiazinane SC_1308 ¹H NMR (600 MHz, 547.3 Dimethylamino-3-1,1-dioxide DMSO) δ 7.35 (qd, 4H), [2-(1,1-dioxo- 7.26 (tt, 1H), 4.40(s, 2H), [1,4]thiazinan-4- 3.89 (dt, 4H), 3.26 (t, 2H),yl)-2-oxo-ethyl]- 3.11 (d, 2H), 2.64 − 2.58 1-[(1-hydroxy- (m, 2H), 2.45(td, 2H), 2.14 cyclobutyl)- (tt, 2H), 2.03 (td, 2H), 1.98methyl]-8-phenyl- (s, 6H), 1.97 − 1.88 (m, 1,3- 2H), 1.70 − 1.63 (m,1H), diazaspiro[4.5]decane- 1.58 − 1.47 (m, 3H). 2,4-dione SC_1332CIS-2-(8- INT-976 procedure ¹H NMR (CDCl3): δ 8.32 407.2Dimethylamino-2- described (br s, 1H), 7.50 − 7.48 (d, oxo-8-phenyl-1,3-2H), 7.39 − 7.36 (m, 2H), diazaspiro[4.5]decan- 7.33 − 7.26 (m, 5H),7.12 − 3-yl)-N-phenyl- 7.08 (t, 1H), 5.90 (br s, 1H), acetamide 3.90 (s,2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94 − 1.91 (m, 2H), 1.58− 1.53 (m, 2H). SC_1333 CIS-N- INT-991 2- SC_1308 ¹HNMR (DMSO-d6, 400388.3 (Carbamoyl- methylamino- MHz at 100 0C.), δ (ppm) = methyl)-2-[1-acetamide•HCl 7.34 − 7.23 (m, 5H), 6.85 (bs, (cyclopropyl- 2H), 3.94 (s,2H), 3.88 (s, methyl)-8- 2H), 3.26 (s, 2H), 3.00 − 2.99 dimethylamino-2-(m, 2H), 2.95 (s, 3H), 2.61 oxo-8-phenyl-1,3- (d, 2H, J = 13.2 Hz), 2.22(t, diazaspiro[4.5]decan- 2H, J = 12 Hz), 2.06 (s, 6H), 3-yl]-N-methyl-1.47 − 1.38 (m, 4H), 0.98 (m, acetamide 1H), 0.48 (d, 2H, J = 7.6 Hz),0.28 (d, 2H, 4.8 Hz). SC_1334 CIS-2-(8- INT-1018 2-Bromo-N- SC_1332 ¹HNMR (DMSO-d6): δ 421.2 Dimethylamino- phenylacetamide 10.19 (s, 1H),8.80 (br s, 2,4-dioxo-8- 1H), 7.52 − 7.520 (d, 2H), phenyl-1,3- 7.42 −7.34 (m, 4H), 7.31 − diazaspiro[4.5]decan- 7.27 (m, 3H), 7.06 − 7.023-yl)-N-phenyl- (t, 1H), 4.11 (s, 2H), 2.49 − acetamide 2.45 (m, 2H),2.03 − 1.93 (m, 8H), 1.71 − 1.68 (m, 2H), 1.60 − 1.54 (m, 2H). SC_1335CIS-2-[1- INT-998 NH₄Cl SC_1308 ¹H NMR (DMSO-d6): δ 399.3 (Cyclobutyl-7.36 − 7.22 (m, 6H), 6.93 (br methyl)-8- s, 1H), 3.61 (s, 2H), 3.18 (s,dimethylamino-2- 2H), 3.04 (d, 2H), 2.66 − 2.63 oxo-8-phenyl-1,3- (m,2H), 2.54 − 2.52 (m, 1H), diazaspiro[4.5]decan- 2.07 − 1.93 (m, 10H),1.81 − 3-yl]-acetamide 1.67 (m, 4H), 1.39 − 1.29 (m, 4H). SC_1336CIS-2-[8- INT-1019 2,5,8,11- SC_1308 ¹H NMR (DMSO-d6): δ 605.3Dimethylamino-1- tetraoxatridecan- 7.37 − 7.33 (m, 2H), 7.28 −[(1-hydroxy- 13-amine 7.26 (m, 3H), 6.67 (t, 1H), cyclobutyl)- 6.31 (br,s, 1H), 3.83 (s, methyl]-2-oxo-8- 2H), 3.65 − 3.59 (m, 10H), phenyl-1,3-3.55 − 3.52 (m, 4H), 3.46 − diazaspiro[4.5]decan- 3.42 (m, 2H), 3.37 (s,5H), 3-yl]-N-[2-[2- 3.29 (s, 2H), 2.68 − 2.65 (m, [2-(2-methoxy- 2H),2.20 − 2.06 (m, 12H), ethoxy)-ethoxy]- 1.78 − 1.71 (m, 1H), 1.59 −ethoxy]-ethyl]- 1.56 (m, 2H), 1.48 − 1.37 acetamide (m, 3H). SC_1337CIS-3-[2-(1,1- SC_1331 SC_1303 ¹H NMR (600 MHz, 533.3 Dioxo- DMSO) δ7.46 (d, 2H), 7.33 [1,4]thiazinan-4- (t, 2H), 7.21 (t, 1H), 4.42 (s,yl)-2-oxo-ethyl]- 2H), 3.90 (dt, 4H), 3.49 (s, 1-[(1-hydroxy- 2H), 3.28(t, 2H), 3.12 (t, cyclobutyl)- 2H), 2.47 (dd, 2H), 2.35 − methyl]-8-2.25 (m, 2H), 2.15 − 2.08 methylamino-8- (m, 2H), 1.98 − 1.89 (m,phenyl-1,3- 6H), 1.84 (d, 2H), 1.71 − diazaspiro[4.5]decane- 1.63 (m,1H), 1.58 − 1.48 2,4-dione (m, 3H). SC_1338 CIS-2-(8- INT-976 2-bromo-N-SC_1332 ¹H NMR (DMSO-d6): δ 521.3 Dimethylamino-2- (2,5,8,11- 7.78 (t,1H), 7.37 − 7.23 (m, oxo-8-phenyl-1,3- tetraoxatridecan- 5H), 6.89 (brs, 1H), 3.60 diazaspiro[4.5]decan- 13-yl)acetamide (s, 2H), 3.49 − 3.47(m, 10H), 3-yl)-N-[2-[2- 3.43 − 3.37 (m, 4H), 3.22 − [2-(2-methoxy- 3.17(m, 5H), 3.08 (s, 2H), ethoxy)-ethoxy]- 2.30 (br m, 2H), 1.92 − 1.74ethoxy]-ethyl]- (m, 10H), 1.38 (br m, 2H). acetamide SC_1339 CIS-N-INT-1034 2- SC_1308 ¹HNMR (DMSO-d6, 400 388.3 (Carbamoyl- methylamino-MHz at 100 0C.), δ (ppm) = methyl)-N- acetamide•HCl 7.43 (d, 2H, J =7.52 Hz), methyl-2-(8- 7.31 (t, 2H, J = 7.44 Hz), methylamino-2- 7.18(t, 1H, J = 7.20 Hz), oxo-8-phenyl-1,3- 6.8 (bs, 2H), 3.88 (s, 4H),diazaspiro[4.5]decan- 3.25 (s, 2H), 2.95 (3H, 3-yl)-acetamide mergedwith DMSO water), 1.97 − 1.85 (m, 7H), 1.77 − 1.50 (m, 4H). SC_1340CIS-N- INT-1014 2-methylamino- SC_1308 ¹HNMR (DMSO-d6, 400 402.1(Carbamoyl- acetamide•HCl MHz at 100 0C.), δ (ppm) = methyl)-2-(8- 7.33− 7.23 (m, 5H), 6.84 (bs, dimethylamino-2- 2H), 6.45 (s, 1H), 3.87 (s,oxo-8-phenyl-1,3- 4H), 3.13 (s, 2H), 2.95 (3H, diazaspiro[4.5]decan-merged with DMSO water), 3-yl)-N- 2.32 − 2.27 (m, 2H), 2.01 (s,methyl-acetamide 6H),1.88 − 1.77 (m, 4H), 1.46 − 1.41 (m, 2H). SC_1341CIS-N- INT-1035 2- SC_1308 ¹HNMR (DMSO-d6, 400 472.3 (Carbamoyl-methylamino- MHz at 100 0C.), δ (ppm) = methyl)-2-[8- acetamide•HCl 7.33− 7.24 (m, 5H), 6.8 (bs, dimethylamino-1- 2H), 4.63 (t, 2H, J = 5.6(oxetan-3-yl- Hz), 4.39 (s, 2H), 3.93 − 3.87 methyl)-2-oxo-8- (m, 4H),3.36 (d, 2H, J = 6.8 phenyl-1,3- Hz), 3.24 (m, 3H), 2.95 (s,diazaspiro[4.5]decan- 3H), 2.66 − 2.60 (m, 2H), 3-yl]-N- 2.06 − 2.03 (m,8H), 1.44 − methyl-acetamide 1.37 (m, 4H). SC_1342 CIS-N-(2- INT-1034 2-SC_1308 ¹HNMR (DMSO-d6, 400 375.0 Hydroxy-ethyl)- (methylamino)- MHz at100 0C.), δ (ppm) = N-methyl-2-(8- ethanol 7.41 (d, 2H, J = 7.48 Hz),methylamino-2- 7.31 (t, 2H, J = 7.60 Hz), oxo-8-phenyl-1,3- 7.18 (t,1H), J = 7.18 Hz), diazaspiro[4.5]decan- 6.24 (s, 1H), 4.58 − 4.36 (m,3-yl)-acetamide 1H), 3.92 (bs, 2H), 3.52 (bs, 2H), 3.34 (t, 2H, J = 5.72Hz), 3.24 (s, 2H), 2.96 − 2.84 (m, 3H), 1.97 − 1.84 (m, 7H), 1.74 − 1.49(m, 4H). SC_1343 CIS-2-[1- INT-991 ammonium SC_1308 ¹H NMR (DMSO d6): δ385.3 (Cyclopropyl- chloride 7.34 − 7.25 (m, 6H), 6.96 (s, methyl)-8-1H), 3.63 (s, 2H), 3.22 (m, dimethylamino-2- 2H), 2.93 (d, 2H), 2.67 −2.64 oxo-8-phenyl-1,3- (m, 2H), 2.16 (t, 2H), 1.97 diazaspiro[4.5]decan-(s, 6H), 1.43 − 1.31 (m, 4H), 3-yl]-acetamide 0.93 (m, 1H), 0.46 − 0.45(m, 2H), 0.26 (m, 2H). SC_1344 CIS-2-[1- INT-991 2- SC_1308 ¹H NMR (DMSOd6): δ 429.3 (Cyclopropyl- aminoethanol 7.77 − 7.75 (m, 1H), 7.36 −methyl)-8- 7.33 (m, 4H), 7.26 − 7.23 (m, dimethylamino-2- 1H), 4.65 −4.63 (m, 1H), oxo-8-phenyl-1,3- 3.67 (s, 2H), 3.39 − 3.35 (m,diazaspiro[4.5]decan- 2H), 3.21 (s, 2H), 3.12 − 3.09 3-yl]-N-(2-hydroxy-(m, 2H), 2.94 − 2.93 (m, 2H), ethyl)-acetamide 2.67 − 2.64 (m, 2H), 2.19− 2.14 (t, 2H), 1.97 (s, 6H), 1.42 − 1.31 (m, 4H), 0.93 − 0.92 (s, 1H),0.48 − 0.44 (m, 2H), 0.27 − 0.25 (m, 2H). SC_1345 CIS-2-[1- INT-1032 2-SC_1308 ¹H NMR (600 MHz, 475.3 (Cyclobutyl- (methylamino)- DMSO) δ 7.39(td, 1H), methyl)-8- ethanol 7.16 (dd, 1H), 7.13 (dt, 2H),dimethylamino-8- 7.08 (td, 1H), 3.99 (s, 1H), (3-fluorophenyl)- 3.91 (s,1H), 3.52 (q, 1H), 2-oxo-1,3- 3.45 (d, 1H), 3.40 − 3.36diazaspiro[4.5]decan- (m, 0H), 3.34 − 3.28 (m, 3-yl]-N-(2- 2H), 3.19 (d,2H), 3.05 (dd, hydroxy-ethyl)-N- 2H), 2.96 (s, 2H), 2.80 (s,methyl-acetamide 2H), 2.66 − 2.60 (m, 3H), 2.07 − 1.93 (m, 3H), 1.99 (s,7H), 1.85 − 1.74 (m, 2H), 1.75 − 1.65 (m, 3H), 1.40 − 1.28 (m, 5H).SC_1346 CIS-2-[1- INT-1031 tert-butyl- procedure ¹H NMR (600 MHz, 474.3(Cyclobutyl- bromo acetate described DMSO) δ 7.43 − 7.36 (m, methyl)-8-1H), 7.17 (d, 1H), 7.13 (dt, dimethylamino-8- 1H), 7.09 (td, 1H), 3.75(d, (3-fluorophenyl)- 2H), 3.21 (s, 2H), 3.05 (d, 2-oxo-1,3- 2H), 2.67 −2.61 (m, 2H), diazaspiro[4.5]decan- 2.08 − 2.00 (m, 2H), 1.993-yl]-acetic (d, 7H), 1.98 − 1.93 (m, acid tert-butyl 2H), 1.83 − 1.75(m, 2H), ester 1.75 − 1.65 (m, 2H), 1.39 (d, 8H), 1.38 − 1.29 (m, 5H).SC_1347 CIS-2-[1- INT-991 2- SC_1308 ¹H NMR (DMSO): δ 7.36 − 444.3(Cyclopropyl- (methylamino)- 7.32 (m, 4H), 7.26 − 7.23 (m, methyl)-8-ethanol 1H), 4.83 − 4.63 (m, 1H), dimethylamino-2- 3.99 − 3.91 (m, 2H),3.50 − oxo-8-phenyl-1,3- 3.44 (m, 2H), 3.32 − 3.28 (m,diazaspiro[4.5]decan- 2H), 3.22 − 3.20 (m, 2H), 3-yl]-N-(2- 2.95 − 2.92(m, 3H), 2.79 (s, hydroxy-ethyl)-N- 2H), 2.67 − 2.65 (m, 2H),methyl-acetamide 2.20 − 2.15 (m, 2H), 1.97(s, 6H), 1.42 − 1.30 (m, 4H),0.93 − 0.90 (s, 1H), 0.47 − 0.43 (m, 2H), 0.27 − 0.25 (m, 2H). SC_1348CIS-2-[1- INT-991 2- SC_1308 ¹H NMR (DMSO): δ 8.05 − 491.3 (Cyclopropyl-(methyl 8.02 (m, 1H), 7.37 − 7.32 (m, methyl)-8- sulfonyl)ethan- 4H),7.26 − 7.22 (m, 1H), dimethylamino-2- amine 3.67 (s, 2H), 3.49 − 3.44(m, oxo-8-phenyl-1,3- 2H), 3.25 − 3.21 (m, 4H), diazaspiro[4.5]decan-2.98 − 2.93 (m, 5H), 2.67 − 3-yl]-N-(2- 2.64 (m, 2H), 2.19 − 2.13 (m,methylsulfonyl- 2H), 1.97 (s, 6H), 1.45 − 1.31 ethyl)-acetamide (m, 4H),0.95 − 0.91 (s, 1H), 0.48 − 0.44 (m, 2H), 0.28 − 0.24 (m, 2H). SC_1349CIS-N- INT-1032 2- SC_1308 1H NMR (600 MHz, 488.3 (Carbamoyl-methylamino- DMSO) δ 7.39 (td, 1H), methyl)-2-[1- acetamide 7.31 (s,1H), 7.19 − 7.05 (cyclobutyl- hydrochloride (m, 3H), 6.99 (s, 1H),methyl)-8- 4.00 − 3.78 (m, 4H), 3.18 dimethylamino-8- (d, 2H), 3.07 −3.02 (m, 2H), (3-fluorophenyl)- 2.94 (s, 2H), 2.76 (s, 1H), 2-oxo-1,3-2.66 − 2.59 (m, 2H), 2.06 − diazaspiro[4.5]decan- 1.93 (m, 9H), 1.84 −1.73 3-yl]-N- (m, 2H), 1.70 (dt, 2H), methyl-acetamide 1.43 − 1.28 (m,4H) (mixture of amide rotamers) SC_1350 CIS-1-[2-[8- INT-1019piperidine-4- SC_1308 1H NMR (DMSO d6): δ 526.4 Dimethylamino-1-carboxamide 7.37 − 7.25 (m, 6H), 6.77 (s, [(1-hydroxy- 1H), 6.02 (s,1H), 4.26 − 4.23 cyclobutyl)- (m, 1H), 4.02 − 3.91 (m, 2H),methyl]-2-oxo-8- 3.79 − 3.75 (m, 1H), 3.31 (m, phenyl-1,3- 2H), 3.10 (s,2H), 3.00 − 2.93 diazaspiro[4.5]decan- (t, 1H), 2.68 − 2.65 (m, 2H),3-yl]-acetyl]- 2.60 − 2.58 (m, 2H), 2.32 − piperidine-4- 2.27 (m, 2H),2.06 − 2.03 (m, carboxylic acid 4H), 1.91 − 1.83 (m, 8H), amide 1.67 −1.61 (m, 2H), 1.49 − 1.40 (m, 2H), 1.36 − 1.30 (m, 4H). SC_1351 CIS-8-INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 561.3 Dimethylamino-1- (methyl-7.37 − 7.23 (m, 5H), 6.00 (s, [(1-hydroxy- sulfonyl)piper- 1H), 4.45 −4.41 (m, 1H), cyclobutyl)- idine 4.08 − 3.91 (m, 3H), 3.17 (s,methyl]-3-[2-(4- 3H), 3.10 − 2.99 (m, 2H), methylsulfonyl- 2.92 (s, 3H),2.73 − 2.65 (m, piperidin-1-yl)-2- 3H), 2.06 − 1.83 (m, 15H),oxo-ethyl]-8- 1.64 − 1.46 (m, 4H), 1.40 − phenyl-1,3- 1.30 (m, 4H).diazaspiro[4.5]decan- 2-one SC_1352 CIS-2-[1- INT-1032 2- SC_1308 1H NMR(600 MHz, 461.3 (Cyclobutyl- aminoethanol DMSO) δ 7.73 (t, 1H), 7.39methyl)-8- (td, 1H), 7.19 − 7.05 (m, dimethylamino-8- 3H), 4.66 (t, 1H),3.67 (s, (3-fluorophenyl)- 2H), 3.43 − 3.35 (m, 2H), 2-oxo-1,3- 3.18 (s,2H), 3.11 (q, 2H), diazaspiro[4.5]decan- 3.05 (d, 2H), 2.65 − 2.583-yl]-N-(2- (m, 2H), 2.55 − 2.45 (m, hydroxy-ethyl)- 1H), 2.07 − 1.93(m, 10H), acetamide 1.84 − 1.73 (m, 2H), 1.74 − 1.64 (m, 2H), 1.41 −1.29 (m, 4H). SC_1353 TRANS-2-[1- INT-1067 2- SC_1357 1HNMR at 100oC.(DMSO- 443.1 (Cyclobutyl- aminoethanol d6, 400 MHz), δ (ppm) =methyl)-8- 7.44 − 7.38 (m, 5H), 7.29 (t, dimethylamino-2- 1H, J = 6.48Hz), 4.29 (bs, oxo-8-phenyl-1,3- 1H), 3.69 (s, 2H), 3.48 − 3.44diazaspiro[4.5]decan- (m, 2H), 3.28 (s, 2H), 3.21 − 3-yl]-N-(2- 3.17 (m,2H), 2.69 − 2.67 (m, hydroxy-ethyl)- 2H), 2.58 − 2.55 (d, 2H, J =acetamide 11.6 Hz), 2.19 − 2.12 (m, 1H), 1.98 (s, 6H), 1.82 − 1.74 (m,2H), 1.71 − 1.60 (m, 4H), 1.58 − 1.46 (m, 6H). SC_1354 TRANS-N- INT-10672- SC_1357 1HNMR at 100oC. (DMSO- 470.4 (Carbamoyl- methylamino- d6, 400MHz), δ (ppm) = methyl)-2-[1- acetamide 7.40 − 7.28 (m, 5H), 6.87 (bs,(cyclobutyl- hydrochloride 2H), 3.94 − 3.90 (m, 4H), methyl)-8- 3.29 (s,2H), 3.68 − 3.66 (m, dimethylamino-2- 2H), 2.58 − 2.55 (m, 2H),oxo-8-phenyl-1,3- 2.15 − 2.13 (m, 1H), 1.98 (s, diazaspiro[4.5]decan-6H), 1.77 (bs, 2H), 1.64 − 3-yl]-N-methyl- 1.61 (m, 4H), 1.46 − 1.27 (m,acetamide 6H). SC_1355 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ513.4 Dimethylamino-1- methylpiperidin- 7.36 − 7.32 (m, 4H), 7.26 −[(1-hydroxy- 4-ol 7.23 (m, 1H), 6.02 (s, 1H), cyclobutyl)- 4.37 (s, 1H),3.96 − 3.95 (m, methyl]-3-[2-(4- 2H), 3.90 − 3.80 (m, 1H), hydroxy-4-3.50 − 3.40 (m, 1H), 3.30 (m, methyl-piperidin- 1H), 3.10 (s, 2H), 3.00− 2.93 1-yl)-2-oxo- (m, 1H), 2.68 − 2.65 (m, 2H), ethyl]-8-phenyl- 2.09− 2.04 (m, 4H), 1.97 (s, 1,3- 6H), 1.90 − 1.86 (m, 2H),diazaspiro[4.5]decan- 1.64 − 1.61 (m, 1H), 1.48 − 2-one 1.40 (m, 5H),1.37 − 1.30 (m, 4H), 1.22 (m, 2H), 1.11 (s, 3H). SC_1356 CIS-2-[1-INT-1058 2- SC_1308 1H NMR (600 MHz, 461.3 (Cyclobutyl- aminoethanolDMSO) δ 7.72 (t, 1H), methyl)-8- 7.40 − 7.33 (m, 2H), 7.15dimethylamino-8- (t 2H), 4.81 (tdd, 0.15H), 4.65 (4-fluorophenyl)- (ddq,0.75H), 3.66 (s, 2H), 2-oxo-1,3- 3.48 (q), 3.25 (q), 3.17 (s,diazaspiro[4.5]decan- 2H), 3.11 (q, 2H), 3.05 (d, 3-yl]-N-(2- 2H), 2.66− 2.60 (m, 2H), hydroxy-ethyl)-acetamide 2.57 − 2.47 (m, 1H), 2.06 −1.92 (m, 10H), 1.85 − 1.73 (m, 2H), 1.75 − 1.63 (m, 2H), 1.40 − 1.28 (m,4H). Not all signals could be intergrated due to overlap with solventpeaks; two rotamers observed in spectrum. SC_1357 TRANS-1- INT-1062morpholine procedure 1HNMR (DMSO-d6, 400 455.1 (Cyclopropyl- describedMHz), δ (ppm) = 7.44 − 7.29 methyl)-8- (m, 5H), 3.96 (s, 2H), 3.56dimethylamino-3- (bs, 4H), 3.42 − 3.40 (m, 4H), (2-morpholin-4- 3.29 (s,2H), 2.67 (bs, 2H), yl-2-oxo-ethyl)-8- 2.55 − 2.54 (d, 2H, J = 6.36phenyl-1,3- Hz), 1.92 (s, 6H), 1.56 − .144 diazaspiro[4.5]decan- (m,6H), 0.51 − 0.48 (m, 2-one 1H), 0.16 − 0.14 (m, 2H), (−0.26) − (−0.27)(m, 2H). SC_1358 TRANS-8- INT-1060 morpholine SC_1357 1HNMR (DMSO-d6,400 401.3 Dimethylamino-3- MHz at 100 0C.), δ (ppm) = (2-morpholin-4-7.39 − 7.36 (m, 4H), 7.26 − yl-2-oxo-ethyl)-8- 7.23 (m, 1H), 6.35 (m,1H), phenyl-1,3- 3.91 (s, 2H), 3.59 (t, 4H, J = diazaspiro[4.5]decan-4.8 Hz), 3.45 (t, 4H, J = 4.8 2-one Hz), 3.27 (s, 2H), 2.18 − 2.15 (m,2H), 2.0 − 1.99 (m, 8H), 1.78 − 1.73 (m, 2H), 1.48 − 1.43 (m, 2H).SC_1359 CIS-2-[1- INT-1058 2- SC_1308 1H NMR (600 MHz, 475.3(Cyclobutyl- (methyl- DMSO) δ 7.37 (dd, 2H), methyl)-8- amino)ethanol7.15 (t, 2H), 4.82 (t, 0.2H), dimethylamino-8- 4.63 (t, 0.2H), 3.98 (s,1H), (4-fluorophenyl)- 3.91 (s, 1H), 3.51 (q, 1H), 2-oxo-1,3- 3.45 (q,1H), 3.37 − 3.26 diazaspiro[4.5]decan- (m, 2H), 3.18 (d, 2H), 3.043-yl]-N-(2- (dd, 2H), 2.96 (s, 1H), 2.80 hydroxy-ethyl)-N- (s, 2H), 2.64(d, 2H), 2.56 − methyl-acetamide 2.47 (m, 1H), 2.08 − 2.00 (m, 2H), 2.00− 1.91 (m, 8H), 1.79 (ddt, 2H), 1.75 − 1.65 (m, 2H), 1.37 (d, 2H), 1.31(td, 2H). Two rotamers are observed. SC_1360 CIS-N- INT-1058 2- SC_13081H NMR (600 MHz, 488.3 (Carbamoyl- methylamino- DMSO) δ 7.46 (s, 0.4H),methyl)-2-[1- acetamide 7.37 (dd, 2H), 7.30 (s, (cyclobutyl-hydrochloride 0.6H), 7.20 − 7.12 (m, 2H), methyl)-8- 6.99 (s, 0.6H),3.97 (s, 1H), dimethylamino-8- 3.90 (s, 1H), 3.83 (d, 2H),(4-fluorophenyl)- 3.18 (d, 2H), 3.04 (dd, 2H), 2-oxo-1,3- 2.94 (s, 2H),2.76 (s, 1H), diazaspiro[4.5]decan- 2.67 − 2.60 (m, 2H), 2.57 − 3-yl]-N-2.47 (m, 1H), 2.07 − 1.92 methyl-acetamide (m, 10H), 1.83 − 1.74 (m,2H), 1.74 − 1.63 (m, 2H), 1.40 − 1.27 (m, 4H). Two rotamers areobserved. SC_1361 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 483.4(Cyclopropyl- hydro- methyl- 7.36 − 7.33 (m, 4H), 7.25 − methyl)-8-chloride piperidin-4-ol 7.23 (m, 1H), 4.37 (s, 1H), dimethylamino-3-3.92 − 3.84 (m, 3H), 3.48 − [2-(4-hydroxy-4- 3.46 (m, 1H), 3.25 − 3.21(m, methyl-piperidin- 3H), 2.99 − 2.92 (m, 3H), 1-yl)-2-oxo- 2.67 − 2.64(m, 2H), 2.20 − ethyl]-8-phenyl- 2.15 (t, 2H), 1.97 (s, 6H), 1,3- 1.44 −1.21 (m, 8H), 1.11 (s, diazaspiro[4.5]decan- 3H), 0.93 − 0.92 (m, 1H),2-one 0.47 − 0.45 (m, 2H), 0.44 − 0.43 (m, 2H). SC_1362 CIS-1-[2-[1-INT-991 piperidine-4- SC_1308 1H NMR (DMSO): δ 7.34 − 496.4(Cyclopropyl- hydro- carboxamide 7.32 (m, 4H), 7.25 − 7.24 (m,methyl)-8- chloride 2H), 6.77 (s, 1H), 4.21 − 4.29 dimethylamino-2- (m,1H), 3.94 − 3.86 (m, 2H), oxo-8-phenyl-1,3- 3.78 (m, 1H), 3.22 (s, 2H),diazaspiro[4.5]decan- 2.96 − 2.93 (m, 3H), 2.67 − 3-yl]-acetyl]- 2.57(m, 2H), 2.50 (t, 1H), piperidine-4- 2.30 (m, 1H), 2.20 − 2.15 (m,carboxylic acid 2H), 1.97 (s, 6H), 1.69 − 1.67 amide (m, 2H), 1.42 −1.31 (m, 6H), 0.92 (m, 1H), 0.47 − 0.43 (m, 2H), 0.27 − 0.24 (m, 2H).SC_1363 TRANS-2-[1- INT-1061 t-butyl- procedure 1HNMR at 100oC. (DMSO-385.2 (Cyclopropyl- bromoacetate described d6, 400 MHz), δ (ppm) =methyl)-8- (step 1), 7 N 7.40 − 7.29 (m, 5H), 6.76 (bs, dimethylamino-2-ammonia in 2H), 3.68 (s, 2H), 3.33 (s, oxo-8-phenyl-1,3- methanol 2H),2.61 − 2.60 (m, 4H), diazaspiro[4.5]decan- (step 2) 2.00 (s, 6H), 1.61 −.153 (m, 3-y]- 6H), 0.58 − 0.56 (m, 1H), acetamide 0.22 − 0.20 (m, 2H),(−0.16) − (−0.18) (m, 2H). SC_1364 TRANS-2-[1- INT-1062 methylamineSC_1357 1HNMR at 100oC. (DMSO- 399.2 (Cyclopropyl- d6, 400 MHz), δ (ppm)= methyl)-8- 7.43 − 7.27 (m, 6H), 3.68 (s, dimethylamino-2- 2H), 3.32(s, 2H), 2.64 − 2.58 oxo-8-phenyl-1,3- (m, 7H), 1.99 (s, 6H), 1.66 −diazaspiro[4.5]decan- .152 (m, 6H), 0.58 − 0.56 (m, 3-yl]-N- 1H), 0.23 −0.19 (m, 2H), methyl-acetamide (−0.15) − (−0.17) (m, 2H). SC_1365TRANS-1- INT-1062 1,4-thiazinane SC_1357 1HNMR at 100oC. (DMSO- 503.3(Cyclopropyl- 1,1-dioxide d6, 400 MHz), δ (ppm) = methyl)-8- 7.40 − 7.28(m, 5H), 4.06 (s, dimethylamino-3- 2H), 3.90 − 3.88 (m, 4H),[2-(1,1-dioxo- 3.34 (s, 2H), 3.14 (bs, 4H), [1,4]thiazinan-4- 2.66 −2.60 (m, 4H), 1.99 (s, yl)-2-oxo-ethyl]- 6H), 1.63 − .152 (m, 6H),8-phenyl-1,3- 0.58-0.56 (m, 1H), 0.23 − diazaspiro[4.5]decan- 0.20 (m,2H), (−0.16) − 2-one (−0.17) (m, 2H). SC_1366 CIS-1- INT-991 4- SC_13081H NMR (DMSO d6): δ 531.4 (Cyclopropyl- hydro- (methyl 7.36 − 7.32 (m,4H), 7.26 − methyl)-8- chloride sulfonyl)piper- 7.23 (m, 1H), 4.40 (m,1H), dimethylamino-3- idine 4.04 − 3.88 (m, 3H), 3.31 (m, [2-(4- 1H),3.02 (s, 2H), 2.94 (t, methylsulfonyl- 1H), 2.94 − 2.92 (m, 5H),piperidin-l-yl)-2- 2.67 − 2.50 (m, 3H), 2.20 − oxo-ethyl]-8- 2.15 (m,2H), 2.08 − 1.97 (m, phenyl-1,3- 8H), 1.56 (m, 1H), 1.42 −diazaspiro[4.5]decan- 1.31 (m, 5H), 0.92 (m, 1H), 2-one 0.47 − 0.43 (m,2H), 0.27 − 0.24 (m, 2H). SC_1368 CIS-8- INT-1019 1,4-thiazinane SC_13081H NMR (600 MHz, 533.3 Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (d,4H), [2-(1,1-dioxo- 7.29 − 7.22 (m, 1H), 4.09 (s, [1,4]thiazinan-4- 2H),3.83 (dt, 4H), 3.25 − yl)-2-oxo-ethyl]- 3.19 (m, 2H), 3.15 − 3.051-[(1-hydroxy- (m, 4H), 2.72 − 2.65 (m, cyclobutyl)- 2H), 2.12 − 2.04(m, 6H), methyl]-8-phenyl- 1.99 (s, 6H), 1.88 (dt, 2H), 1,3- 1.68 − 1.59(m, 1H), 1.50 diazaspiro[4.5]decan- (d, 2H), 1.43 − 1.29 (m, 2-one 3H).SC_1369 TRANS-2-(8- INT-1060 t-butyl- SC_1363 1HNMR (DMSO-d6, 400 331.2Dimethylamino-2- bromoacetate MHz at 100 0C.), δ (ppm) =oxo-8-phenyl-1,3- (step 1), 7 N 7.37 − 7.24 (m, 5H), 6.74 (bs,diazaspiro[4.5]decan- ammonia in 2H), 6.38 (s, 1H), 3.62 (s,3-yl)-acetamide methanol 2H), 3.27 (s, 2H), 2.19 − 2.14 (step 2) (m,2H), 2.01 − 1.96 (m, 8H), 1.78 − 1.73 (m, 2H), 1.48 − 1.43 (m, 2H).SC_1370 TRANS-8- INT-1060 1,4-thiazinane SC_1357 1HNMR (DMSO-d6, 400449.2 Dimethylamino-3- 1,1-dioxide MHz at 100 0C.), δ (ppm) =[2-(1,1-dioxo- 7.37 − 7.24 (m, 5H), 6.41 (s, [1,4]thiazinan-4- 1H), 4.0(s, 2H), 3.89 (bs, yl)-2-oxo-ethyl]- 4H), 3.28 (s, 2H), 3.14 (bs,8-phenyl-1,3- 4H), 2.15 (m, 2H), 1.99 (m, diazaspiro[4.5]decan- 8H),1.78 − 1.73 (m, 2H), 2-one 1.48 − 1.43 (m, 2H). SC_1371 CIS-8- INT-1068t-butyl- SC_1363 413.2 (dimethylamino)- bromoacetate 8-phenyl-1-(2,2,2-(step 1), 7 N trifluoroethyl)-3- ammonia in (2- methanol (trifluoro-(step 2) methyl)pyrimidin- 5-yl)-1,3- diazaspiro[4.5]decan- 2-oneSC_1372 CIS-8- INT-1070 t-butyl- SC_1363 (dimethylamino)- bromoacetate8-phenyl-3-(2- (step 1), 7 N (trifluoro- ammonia in methyl)pyrimidin-methanol 5-yl)-1-(3,3,3- (step 2) trifluoropropyl)- 1,3-diazaspiro[4.5]decan- 2-one

Chemical Structure of all Examples

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), humankappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), andhuman nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin(Sigma-Aldrich Co., St. Louis, Mo.). The final assay volume (250μl/well) included 1 nM of [N-allyl-2,3-³H]naloxone as ligand(PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either testcompound in dilution series or 25 μM unlabelled naloxone fordetermination of unspecific binding. The test compound was diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration, which alsoserved as a respective vehicle control. The assay was started by addingwheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd.,Buckinghamshire, UK) which had been preloaded with hMOP receptormembranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). Afterincubation for 90 minutes at RT and centrifugation for 20 minutes at 500rpm the signal rate was measured by means of a 1450 Microbeta Triluxβ-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland).Half-maximal inhibitory concentration (IC50) values reflecting 50%displacement of [³H]naloxone-specific receptor binding were calculatedby nonlinear regression analysis and Ki values were calculated by usingthe Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of250 μl per well includes 2 nM of [³H]U69,593 as ligand, and either testcompound in dilution series or 100 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hKOP receptor membranes (14.8 μs/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 90 minutes at room temperature. After this incubation, themicrotiter plates are sealed with a topseal and centrifuged for 20minutes at 500 rpm. The signal rate is measured after a short delay of 5minutes by means of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]U69.593-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assayusing the assay buffer 50 mM TRIS-HCl, 5 mM MgCl₂ (pH 7.4). The finalassay volume (250 μl/well) includes 1 nM of[Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either testcompound in dilution series or 10 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hDOP receptor membranes (15.2 μg/250 IA finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 120 minutes at room temperature and centrifuged for 20minutes at 500 rpm. The signal rate is measured by means of a 1450Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac, Turku,Finland). Half-maximal inhibitory concentration (IC50) values reflecting50% displacement of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl,10 mM MgCl₂, 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well)included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer LifeSciences, Inc. Boston, Mass., USA), and either test compound in dilutionseries or 1 μM unlabelled nociceptin for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration, which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc.Boston, Mass., USA). After incubation for 60 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]nociceptin-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation, (Cheng andPrusoff, 1973).

hNOP hMOP Example Ki [nM] Ki [nM] SC_1001 33 206 SC_1002 2.1 160 SC_10033.7 102 SC_1004 3.6 84 SC_1005 6.3 115.5 SC_1006 2.2 150 SC_1007 29.5190 SC_1008 5.4 117.5 SC_1009 17 390 SC_1010 9.8 175 SC_1011 9.1 112.5SC_1012 1.8 47.5 SC_1013 1 220 SC_1014 2.6 175 SC_1015 1.3 140 SC_10163.1 76.5 SC_1017 2.6 130 SC_1018 2.8 106.5 SC_1019 4.6 170 SC_1020 2 86SC_1021 1.6 94 SC_1022 2.1 20.5 SC_1023 13 270 SC_1024 3.7 26.5 SC_102522 125 SC_1026 2 67.3 SC_1027 7.6 55 SC_1028 4.8 104 SC_1029 52.3 303.3SC_1030 3.1 74.5 SC_1031 3.6 43 SC_1032 4.9 69.5 SC_1033 3.9 75.5SC_1034 2.1 47 SC_1035 1.3 21.5 SC_1036 2.7 39 SC_1037 1.8 45 SC_10381.6 41.5 SC_1039 1.3 34.5 SC_1040 1.1 15 SC_1041 1.7 20.5 SC_1042 1.8 57SC_1043 1.1 21.5 SC_1044 1.7 43 SC_1045 1.6 44.5 SC_1046 2.3 54 SC_10472.5 49 SC_1048 1 43.5 SC_1049 2.9 48.5 SC_1050 0.8 40 SC_1051 1.6 36.5SC_1052 1.6 24.5 SC_1053 2.7 53 SC_1054 2.6 74.5 SC_1055 2.5 29 SC_10563.3 10 SC_1057 1.9 11 SC_1058 2.9 78 SC_1059 7.4 45 SC_1060 5.1 40.5SC_1061 2.2 12.6 SC_1062 2.6 47.5 SC_1063 1.6 22 SC_1064 4.2 33 SC_10654.8 26.5 SC_1066 1.9 23 SC_1067 7.5 31.5 SC_1068 68.5 360 SC_1069 1.416.5 SC_1070 1 13.5 SC_1071 3.6 38.5 SC_1072 2.8 62 SC_1073 3.5 25SC_1074 5.9 37 SC_1075 1.5 19.5 SC_1076 0.8 72 SC_1077 1.8 20.5 SC_10781.3 23.3 SC_1079 1.7 26.2 SC_1080 6.4 19.5 SC_1081 1.9 64 SC_1082 1 81.5SC_1083 1.5 44 SC_1084 1.1 59 SC_1085 3.8 71 SC_1086 0.8 16.5 SC_10872.4 28.2 SC_1088 2 19.5 SC_1089 1.4 16.5 SC_1090 3 27.5 SC_1091 1.3 15.5SC_1092 1.8 26.5 SC_1093 4.2 43 SC_1094 2.8 10.4 SC_1095 1.8 12.5SC_1096 1.6 12 SC_1097 1.6 15 SC_1098 1.5 10 SC_1099 1.5 4.5 SC_1100 12.3 SC_1101 3.4 6 SC_1102 2 4.4 SC_1103 0.4 7.2 SC_1104 1.2 23 SC_1105 450.5 SC_1106 11 122 SC_1107 1.8 45 SC_1109 2.8 16 SC_1110 9.8 31.5SC_1111 1.6 30 SC_1112 1.3 30.5 SC_1113 0.8 30 SC_1114 109.5 850 SC_1115140 145 SC_1117 4.1 37.5 SC_1118 2.4 114.3 SC_1119 6.5 73.5 SC_1120 2.9125 SC_1121 115 630 SC_1122 124.5 480 SC_1123 2.6 24.8 SC_1124 1.8 33.8SC_1125 2.2 23 SC_1126 3.5 29.5 SC_1127 2.6 2.7 SC_1128 1.9 72 SC_11291.7 37.3 SC_1130 68.5 160 SC_1131 34.5 215 SC_1132 23.5 410 SC_1133 6.425.5 SC_1134 26 140 SC_1135 73 370 SC_1136 14 57.5 SC_1137 5.8 99SC_1138 0.9 23.5 SC_1139 215 515 SC_1140 51.5 150 SC_1141 4.8 165SC_1142 265 1200 SC_1143 17 200 SC_1144 9.8 73.5 SC_1145 3.4 60.5SC_1146 2.2 21.2 SC_1147 2.6 34.2 SC_1148 40 18.8 SC_1149 62 102.5SC_1150 4.9 55.5 SC_1151 1.6 13.5 SC_1152 0.9 13.7 SC_1153 1.6 37SC_1154 4.5 29 SC_1155 14.1 114.5 SC_1156 155 1215 SC_1157 170 1120SC_1158 12.5 144.5 SC_1159 22.5 81.5 SC_1160 20 84.5 SC_1161 60 86SC_1162 15.3 47.5 SC_1163 30.5 119 SC_1164 8.2 16.5 SC_1165 5.7 63.5SC_1166 17 72.5 SC_1167 18 92 SC_1168 37 125 SC_1169 36.5 370 SC_1171 43130 SC_1172 27.5 106 SC_1173 38.5 120 SC_1174 12.9 195 SC_1175 28.5 9.6SC_1176 9 56 SC_1177 39 660 SC_1178 16 390 SC_1179 87.5 180 SC_1180 80230 SC_1181 125 435 SC_1182 47.5 320 SC_1183 130 185 SC_1184 110 153.3SC_1185 47 165 SC_1186 95.5 355 SC_1187 43 127.5 SC_1188 9.1 175 SC_118970.5 75.5 SC_1190 11.2 123.5 SC_1191 29 150 SC_1192 17 680 SC_1193 9.941 SC_1195 4.4 6.2 SC_1196 2.1 64.8 SC_1197 5.4 60 SC_1198 4.9 47SC_1199 35 230 SC_1201 13.3 123.7 SC_1203 5.2 47.5 SC_1204 2.5 77.2SC_1205 2.2 37 SC_1206 1.2 61.5 SC_1207 2.9 38 SC_1208 1.8 90 SC_12093.2 46 SC_1210 4.4 83.5 SC_1211 2.4 18.7 SC_1212 4.8 37.7 SC_1213 1.831.7 SC_1214 1 56.7 SC_1215 3.9 25 SC_1216 1.2 49 SC_1217 2.2 25.7SC_1218 5.2 59 SC_1219 4.2 73.7 SC_1220 4 51 SC_1221 17 180 SC_1222 2.663 SC_1223 2.5 43.5 SC_1224 1.6 15 SC_1225 1.8 49.5 SC_1226 2.6 12.5SC_1227 4.6 63 SC_1228 665 1740 SC_1229 2.8 22.5 SC_1230 1.5 36.5SC_1231 2 51.5 SC_1232 1.4 32.5 SC_1233 0.5 26.5 SC_1234 1.8 53.5SC_1236 3.3 83 SC_1300 13 130 SC_1301 23 44 SC_1302 27 66.5 SC_1303 145215 SC_1304 280 400 SC_1305 19 105.5 SC_1306 59 45 SC_1308 22 97 SC_130912.5 100 SC_1310 8.1 17 SC_1311 11.5 44 SC_1312 295 520 SC_1313 305 1015SC_1317 1.4 53.5 SC_1318 89 960 SC_1319 4 71 SC_1320 4 51 SC_1321 17 180SC_1322 6%@1 μM 9%@1 μM SC_1323 12%@1 μM 7%@1 μM SC_1324 330 6025SC_1325 0%@1 μM 5%@1 μM SC_1326 0%@1 μM 625 SC_1327 11 120 SC_1328 2%@1μM 6%@1 μM SC_1329 0%@1 μM 4%@1 μM SC_1330 465 18%@1 μM SC_1331 10 38SC_1332 52 1950 SC_1333 36 300 SC_1334 195 1605 SC_1335 2 24 SC_1336 — —SC_1337 23 — SC_1338 475 14%@1 μM SC_1339 1110 9%@1 μM SC_1340 230 14%@1μM SC_1341 170 2905 SC_1342 1140 10%@1 μM SC_1343 12 95 SC_1344 13 145SC_1345 1 185 SC_1346 2 400 SC_1347 31 615 SC_1348 8 97 SC_1349 1 165SC_1350 8 510 SC_1351 1 235 SC_1352 1 135 SC_1353 66 80.5 SC_1354 465210 SC_1355 7 325 SC_1356 11 86 SC_1357 100 15.5 SC_1358 73 51.5 SC_135910 260 SC_1360 15 180 SC_1361 13 255 SC_1362 6 240 SC_1363 185 225SC_1364 230 73.5 SC_1365 160 4.4 SC_1366 1 205 SC_1368 7 360 SC_1369 4651805 SC_1370 100 11

Protocol for [³⁵S]G-TPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO-K1 cells transfected with the humanMOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No.RBHODM), and HEK293 cells transfected with the human NOP receptor(Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) areavailable from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cellstransfected with the human nociceptin/orphanin FQ peptide (hNOP)receptor (Art.-No. 93-0264C₂, DiscoveRx Corporation, Freemont, Calif.)are also used. [³⁵S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham,Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillenet al (2000). They are run as homogeneous scintillation proximity (SPA)assays in microtiter luminescence plates, where each well contains 1.5mg of WGA-coated SPA-beads. To test the agonistic activity of testcompounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressingcell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane proteinper assay are incubated with 0.4 nM [³⁵S]GTPγS and serial concentrationsof receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4,100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃,and 10 μM GDP for 45 min at room temperature. The microtiter plates arethen centrifuged for 10 min at 830 to sediment the SPA beads. Themicrotiter plates are sealed and the bound radioactivity [cpm] isdetermined after a delay of 15 min by means of a 1450 Microbeta Trilux(PerkinElmer, Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determinedfrom 12 unstimulated incubates and is set as 100% basal binding. Fordetermination of the potency and the efficacy, the arithmetic mean ofthe observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates(duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ,SNC80, DAMGO, or U69,593) are transformed in percent total binding(TB_(obs) [%]) relative to the basal binding activity (i.e. 100%binding). The potency (EC50) of the respective agonist and its maximalachievable total [³⁵S]GTPγS binding (TB_(calc) [%]) above its calculatedbasal binding (UBS_(calc) [%]) are determined from its transformed data(TB_(obs) [%]) by means of nonlinear regression analysis with XLfit foreach individual concentration series. Then the difference between thecalculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and themaximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by eachtested agonist is determined (i.e. B1_(calc) [%]). This difference(B1_(calc) [%]) as a measure of the maximal achievable enhancement of[³⁵S]GTPγS binding by a given agonist is used to calculate the relativeefficacy of test compounds versus the maximal achievable enhancement bya receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) whichis set as 100% relative efficacy for the hNOP receptor. Likewise, thepercentage efficacies of test compounds at the hDOP, hMOP, or hKOPreceptor are determined versus the calculated maximal enhancement of[³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) [%]),DAMGO (B1_(calc-DAMGO) [%] and U69,593 (B1_(calc-U69,593) [%]) which areset as 100% relative efficacy at each receptor, respectively.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A compound according to general formula (I)

wherein R¹ and R² independently of one another mean —H; —C₁-C₆-alkyl,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —OH,—OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered heterocycloalkyl moiety is optionally connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or R¹ and R² together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 6-14-membered aryl moiety is optionallyconnected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; X means —O—, —S—or —NR⁶—; R⁵ means —H; —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; incase X means NR⁶, R⁶ means —H; —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; or incase X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independentlyof one another mean —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein “mono- or polysubstituted” means that one ormore hydrogen atoms are replaced by a substituent independently of oneanother selected from the group consisting of —F, —Cl, —Br, —I, —CN,—R²¹, —C(═O)R²¹, —C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀, —CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹,—OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²²,—NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²¹—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²²,—NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²; wherein R²¹, R²² and R²³independently of one another mean —H; —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, and—O—C₁-C₆-alkyl; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; a 3-12-membered heterocycloalkyl moiety, saturatedor unsaturated, unsubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²²,—NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═)NR²¹R²², or—S(═O)₂NR²¹R²² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein RB means —H or —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; or aphysiologically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,and R²⁰ independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl.3. The compound according to claim 1, wherein R¹ means —H; and R² means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 4. The compound according toclaim 1, wherein R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 5. The compound according to claim 1, wherein R¹ means—H or —CH₃; and wherein R² means —CH₂-cycloalkyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-oxetanyl or —CH₂-tetrahydrofuranyl.
 6. Thecompound according to claim 1, wherein R¹ and R² together with thenitrogen atom to which they are attached form a ring and mean—(CH₂)₃₋₆—.
 7. The compound according to claim 1, wherein R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 8. The compound according toclaim 1, wherein R³ means a 6-14-membered aryl moiety, unsubstituted,mono- or polysubstituted.
 9. The compound according to claim 1, whereinR³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted.
 10. The compound according to claim 1, wherein R⁴ means—H.
 11. The compound according to claim 1, wherein R⁴ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 12. The compound according toclaim 1, wherein R⁴ means a 3-12-membered cycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 13. The compound according to claim 1, wherein R⁴ meansa 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 14. The compound according to claim 1, wherein R⁴ meansa 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 15. The compound according toclaim 1, wherein R⁴ means a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted; wherein said 5-14-memberedheteroaryl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 16. The compound according to claim 1, wherein R⁵ means—H.
 17. The compound according to claim 1, wherein R⁵ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 18. The compound according toclaim 1, wherein R⁵ means a 3-12-membered cycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted, wherein said3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 19. The compound according toclaim 1, wherein R⁵ means a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;wherein said 3-12-membered heterocycloalkyl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 20. The compoundaccording to claim 1, wherein R⁵ means a 5-14-membered heteroarylmoiety, unsubstituted, mono- or polysubstituted; wherein said5-14-membered heteroaryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 21. The compound according toclaim 1, wherein X means NR⁶ and R⁵ and R⁶ together with the nitrogenatom to which they are attached form a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 22. The compound according to claim 1, wherein X meansNR⁶ and R⁶ means —H or —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 23. The compoundaccording to claim 1, which has a structure according to any of generalformulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, R⁵, R⁶ and X are defined as inclaim 1, R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; R^(D) means —H or—F; or a physiologically acceptable salt thereof.
 24. The compoundaccording to claim 1, wherein the substructure

has a meaning selected from the group consisting of:


25. The compound according to claim 1, wherein R¹ means —H or —CH₃; R²means —CH₃, —CH₂CH₃ or —CH₂—C(H)(CH₃)₂; R³ means -phenyl, -thienyl or-pyridinyl, in each case unsubstituted or monosubstituted with —F; R⁴means —H; —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, ═O, —N(CH₃)₂ and —O—CH₃; or -cyclopropyl, -cyclobutyl, -cyclopentylor -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or—CH₃, wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or-cyclohexyl is connected through —CH₂— or —CH₂CH₂—; -oxetanylunsubstituted or monosubstituted with —F, —OH, —CN or —CH₃, wherein said-oxetanyl is connected through —CH₂— or —CH₂CH₂—; X means —O— or —NR⁶—;R⁵ means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀—H, —O—(CH₂CH₂—O)₁₋₁₀—CH₃,—C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —OH,—S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH₃,—N(CH₃)₂ and NH—S(═O)₂—CH₃; -cyclopropyl, -cyclobutyl, -cyclopentyl or-cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH₃,wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl isoptionally connected through —CH₂— or —CH₂CH₂—; -heterocyclobutyl,-heterocyclopentyl, or -heterocyclohexyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—O—CH₃, —O—(CH₂—CH₂—O)₁₋₁₀, —H, —O—(CH₂CH₂—O)₁₋₁₀—CH₃, —C₁-C₄-alkyl,—C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, ═O, —OH,—SCH₃, —S(═O)CH₃, —S(═O)₂CH₃, unsubstituted —C(═O)-morpholinyl,—NH—C(═O)—CH₃, —N(CH₃)₂ and NH—S(═O)₂—CH₃; wherein said-hetero-cyclobutyl, -heterocyclopentyl, or -heterocyclohexyl isoptionally connected through —CH₂— or —CH₂CH₂—; -oxazolyl, -isoxazolyl,-pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl,-thiadiazolyl, -imidazolyl, -pyrimidinyl, or5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, Br, —I, —CN, —OH, —CH₃, —O—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,—C(═O)NHCH₃, —C(═O)N(CH₃)₂, S(═O)CH₃, —S(═O)₂CH₃ and —S—CH₃, whereinsaid -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl,-pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionallyconnected through —CH₂—; or -phenyl, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH₃,—O—CH₃, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂,S(═O)CH₃, —S(═O)₂ CH₃ and —S—CH₃, wherein said -phenyl is optionallyconnected through —CH₂—; in case X means NR⁶, R⁶ means —H or —CH₃; or incase X means NR⁶, R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a -pyrrolidinyl, -piperidinyl, -piperazinyl,-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or-(methylsulfonyl)piperazinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of ═O, —OH, —CH₂—OH, —C(═O)NH₂, and—S(═O)₂CH₃, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl,-morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or-(methylsulfonyl)piperazinyl is optionally condensed with an imidazolemoiety, unsubstituted; and R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁸, R¹⁹, and R²⁰ mean —H.
 26. The compound according to claim 1, whichhas a structure according to general formula (I′)

wherein R¹ to R⁵, R⁹ to R²⁰, and X are defined as in claim 1, or aphysiologically acceptable salt thereof.
 27. The compound according toclaim 1, which has a structure according to general formula (IX)

wherein R^(C) means —H or —OH; R³ means -phenyl or -3-fluorophenyl; R⁵means —H, —CH₃, —CH₂CH₂OH, or —CH₂C(═O)NH₂; R⁶ means —H or —CH₃; or R⁵and R⁶ together with the nitrogen atom to which they are attached form aring and mean —(CH₂)₅—, wherein said ring is unsubstituted orsubstituted with one or two substituents independently of one anotherselected from the group consisting of —CH₃, —OH, —S(═O)₂CH₃ and—C(═O)NH₂; R⁹ and R¹⁰ independently of one another mean —H or —CH₃; or aphysiologically acceptable salt thereof.
 28. The compound according toclaim 1, which is selected from the group consisting ofCIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylicacid methyl ester;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinicacid methyl ester;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylicacid amide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide;CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinicacid methyl ester;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinicacid methyl ester;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide;CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide;CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylicacid amide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide;CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylicacid amide;CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylicacid amide;CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide;CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide;CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylicacid amide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylicacid amide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide;CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide;CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide;CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide;CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide;CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide;CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylicacid amide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide;CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide;CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide;CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide;CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-acetamide;CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide;CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide;CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-aceticacid tert-butyl ester;CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylicacid amide;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylicacid amide;TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-oneand the physiologically acceptable salts thereof.
 29. The compoundaccording to claim 1 adapted for use in the treatment of pain.
 30. Amedicament comprising a compound according to claim
 1. 31. A method oftreating pain in a patient in need thereof, said method comprisingadministering to said patient an effective amount therefor of at leastone compound according to claim
 1. 32. A method of treating a disorderselected from the group consisting of neurodegenerative disorders,neuroinflammatory disorders, neuropsychiatric disorders, and substanceabuse/dependence, said method comprising administering to a patient inneed thereof an effective amount therefor of at least one compoundaccording to claim 1.